Therapeutic agents useful for treating pain

ABSTRACT

The present invention discloses a compound of formula: 
     
       
         
         
             
             
         
       
     
     where Ar 1 , Ar 2 , X, Z 1 , Z 2 , R 3 , and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Pyridylene Compound”); compositions comprising an effective amount of a Pyridylene Compound; and methods for treating or preventing pain or other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Pyridylene Compound.

This application claims the benefit of U.S. provisional application No.60/504,730, filed Sep. 22, 2003, and International patent applicationno. PCT/US2004/030825, filed Sep. 21, 2004, the disclosure of eachapplication being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Pyridylene Compounds, compositionscomprising an effective amount of a Pyridylene Compound and methods fortreating or preventing a Condition such as pain comprising administeringto an animal in need thereof an effective amount of a PyridyleneCompound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or central nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at both Group I mGluRs (mGluR1 andmGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloidreceptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5reduces pain, as shown by in vivo treatment with antibodies selectivefor either mGluR1 or mGluR5, where neuropathic pain in rats wasattenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It hasalso been shown that antisense oligonucleotide knockdown of mGluR1alleviates both neuropathic and inflammatory pain (M. E. Fundytus etal., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytuset al., Pharmacology, Biochemistry & Behavior 73:401-410 (2002)). Smallmolecule antagonists for mGluR5-attenuated pain in in vivo animal modelsare disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9(2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.,gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDAantagonists (e.g., ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.,fluoxetine, sertraline and amitriptyline).

Pain has been traditionally managed by administering non-opioidanalgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.

Urinary incontinence (“UI”) is uncontrollable urination, generallycaused by bladder-detrusor-muscle instability. UI affects people of allages and levels of physical health, both in health care settings and inthe community at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al, Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects. For example,drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

About 1 in 10 people develop an ulcer. Ulcers develop as a result of animbalance between acid-secretory factors, also known as “aggressivefactors,” such as stomach acid, pepsin, and Helicobacter pyloriinfection, and local mucosal-protective factors, such as secretion ofbicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres toepithelial cells and is believed to form a protective coating at thebase of an ulcer to promote healing. Sucraflate, however, can causeconstipation, dry mouth, and interfere with the absorption of otherdrugs.

Antibiotics are used when Helicobacter pylori is the underlying cause ofthe ulcer. Often antibiotic therapy is coupled with the administrationof bismuth compounds such as bismuth subsalicylate and colloidal bismuthcitrate. The bismuth compounds are believed to enhance secretion ofmucous and HCO₃ ⁻, inhibit pepsin activity, and act as an antibacterialagainst H. pylori. Ingestion of bismuth compounds, however, can lead toelevated plasma concentrations of Bi⁺³ and can interfere with theabsorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acidand stimulate the secretion of mucous and bicarbonate and are also usedto treat ulcers, especially ulcers in patients who require nonsteroidalanti-inflammatory drugs. Effective oral doses of prostaglandinanalogues, however, can cause diarrhea and abdominal cramping. Inaddition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers.Carbenoxolone appears to alter the composition and quantity of mucous,thereby enhancing the mucosal barrier. Carbenoxolone, however, can leadto Na⁺ and fluid retention, hypertension, hypokalemia, and impairedglucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapinecan also be used to reduce acid secretion and treat ulcers. Side effectsof muscarinic cholinergic antagonists include dry mouth, blurred vision,and constipation. The Merck Manual of Medical Information 496-500 (R.Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis ofTherapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominalpain, fever, loss of appetite, and weight loss. Complications associatedwith Crohn's disease include the development of intestinal obstructions,abnormal connecting channels (fistulas), and abscesses. The risk ofcancer of the large intestine is increased in people who have Crohn'sdisease. Often Crohn's disease is associated with other disorders suchas gallstones, inadequate absorption of nutrients, amyloidosis,arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyodermagangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primarysclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine. Generally, the drug is takenorally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptomsof Crohn's disease. The antibiotic metronidazole is often administeredwhen the disease affects the large intestine or causes abscesses andfistulas around the anus. Long-term use of metronidazole, however, candamage nerves, resulting in pins-and-needles sensations in the arms andlegs. Sulfasalazine and chemically related drugs can suppress mildinflammation, especially in the large intestine. These drugs, however,are less effective in sudden, severe flare-ups. Corticosteroids, such asprednisone, reduce fever and diarrhea and relieve abdominal pain andtenderness. Long-term corticosteroid therapy, however, invariablyresults in serious side effects such as high blood-sugar levels,increased risk of infection, osteoporosis, water retention, andfragility of the skin. Drugs such as azathioprine and mercaptourine cancompromise the immune system and are often effective for Crohn's diseasein patients that do not respond to other drugs. These drugs, however,usually need 3 to 6 months before they produce benefits and can causeserious side effects such as allergy, pancreatitis, and lowwhite-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown. Treatmentof ulcerative colitis is directed to controlling inflammation, reducingsymptoms, and replacing lost fluids and nutrients.

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more men than women.

There are two major types of IBS. The first type, spastic-colon type, iscommonly triggered by eating, and usually produces periodic constipationand diarrhea with pain. Mucous often appears in the stool. The pain cancome in bouts of continuous dull aching pain or cramps, usually in thelower abdomen. The person suffering from spastic-colon type IBS can alsoexperience bloating, gas, nausea, headache, fatigue, depression,anxiety, and difficulty concentrating. The second type of IBS usuallyproduces painless diarrhea or constipation. The diarrhea can beginsuddenly and with extreme urgency. Often the diarrhea occurs soon aftera meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the addictive substance.U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixedopiate agonist/antagonist to treat cocaine and opiate addiction. U.S.Pat. No. 5,232,934 to Downs discloses administration of3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and5,198,459 to Imperato et al. disclose using a serotonin antagonist totreat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al.discloses infusing BDNF or NT-4 growth factors to inhibit or reverseneurological adaptive changes that correlate with behavioral changes inan addicted individual. U.S. Pat. No. 5,762,925 to Sagan disclosesimplanting encapsulated adrenal medullary cells into an animal's centralnervous system to inhibit the development of opioid intolerance. U.S.Pat. No. 6,204,284 to Beer et al. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akineticstate in which patients are incapable of caring for themselves. Deathfrequently results from complications of immobility, includingaspiration pneumonia or pulmonary embolism. Drugs commonly used for thetreatment of Parkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

Anxiety is a fear, apprehension or dread of impending danger oftenaccompanied by restlessness, tension, tachycardia and dyspnea.Currently, benzodiazepines are the most commonly used anti-anxietyagents for generalized anxiety disorder. Benzodiazepines, however, carrythe risk of producing impairment of cognition and skilled motorfunctions, particularly in the elderly, which can result in confusion,delerium, and falls with fractures. Sedatives are also commonlyprescribed for treating anxiety. The azapirones, such as buspirone, arealso used to treat moderate anxiety. The azapirones, however, are lessuseful for treating severe anxiety accompanied with panic attacks.

Epilepsy is a disorder characterized by the tendency to have recurringseizures. Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital,phenyloin, primidone, valproic acid, trimethadione, benzodiazepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

Symptoms of strokes vary depending on what part of the brain isaffected. Symptoms include loss or abnormal sensations in an arm or legor one side of the body, weakness or paralysis of an arm or leg or oneside of the body, partial loss of vision or hearing, double vision,dizziness, slurred speech, difficulty in thinking of the appropriateword or saying it, inability to recognize parts of the body, unusualmovements, loss of bladder control, imbalance, and falling, andfainting. The symptoms can be permanent and can be associated with comaor stupor. Examples of drugs for treating strokes include anticoagulantssuch as heparin, drugs that break up clots such as streptokinase ortissue plasminogen activator, and drugs that reduce swelling such asmannitol or corticosteroids. The Merck Manual of Medical Information352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching.Conventionally, pruritus is treated by phototherapy with ultraviolet Bor PUVA or with therapeutic agents such as naltrexone, nalmefene,danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anxiolytic and anti-depressant activity in in vivo animal models(E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) andP. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37(2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4(9):873-74 (2001)).

U.S. Pat. No. 6,495,550 to McNaughton-Smith et al. discloses pyridinesubstituted benzanilides useful as openers of potassium ion channels.

International publication no. WO 94/05153 discloses substituted benzenecompounds useful as herbicides.

International publication no. WO 04/058762 discloses substituted9-membered bicyclic compounds useful as MK-2 inhibitors.

United Kingdom Application No. GB 2 276 162 discloses aniline andbenzanilide compounds useful for treating disorders of the centralnervous system, endocrine disorders, and sexual dysfunction.

United Kingdom Application No. GB 2 276 163 discloses pyridine compoundsuseful for treating disorders of the central nervous system, endocrinedisorders, and sexual dysfunction.

European Application No. EP 533267 discloses benzanilide compoundsuseful as 5-HT1D antagonists.

There remains a need in the art for compounds useful for treating orpreventing pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, amyotrophic lateralsclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting,dyskinesia, or depression in an animal.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds of formula (I):

and pharmaceutically acceptable salts thereof, where

Ar₁ is

Ar₂ is

X is O or S;

R₁ is -halo, —CH₃, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂;    -   (b) -(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) -(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, (C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)        heteroaryl, each of which is unsubstituted or substituted with        one or more R₆ groups;

each R₅ is independently —CN, —OH, —(O—C₆)alkyl, —(C₂-C₆)alkenyl, -halo,—N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 3;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

The invention further encompasses compounds of formula (II):

and pharmaceutically acceptable salts thereof, where

Ar₁ is

Ar₂ is

X is O or S;

R₁ is -halo, —CH₃, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —NH₂, —CN, or —NO₂;    -   (b) -(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) -(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,        —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,        (C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7-        to 10-membered)bicycloheterocycle, each of which is        unsubstituted or substituted with one or more R₅ groups; or    -   (c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)        heteroaryl, each of which is unsubstituted or substituted with        one or more R₆ groups;

each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R_(B), or —S(O)₂R₇;

each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R_(B), or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is an integer ranging from 0 to 3;

n is an integer ranging from 0 to 3;

o is an integer ranging from 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

A compound of formula (I) or (II) or a pharmaceutically acceptable saltthereof (a “Pyridylene Compound”) is useful for treating or preventingpain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson'sdisease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression (eachbeing a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a Pyridylene Compound and a pharmaceutically acceptablecarrier or excipient. The compositions are useful for treating orpreventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a Pyridylene Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a Pyridylene Compound.

The invention still further relates to methods for inhibiting VanilloidReceptor 1 (“VR1”) function in a cell, comprising contacting a cellcapable of expressing VR1 with an effective amount of a PyridyleneCompound.

The invention still further relates to methods for inhibiting mGluR5function in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a Pyridylene Compound.

The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a Pyridylene Compound.

The invention still further relates to methods for preparing acomposition, comprising the step of admixing a Pyridylene Compound and apharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Pyridylene Compound.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Pyridylene Compounds ofFormula (I)

As stated above, the present invention encompasses compounds of Formula(I)

and pharmaceutically acceptable salts thereof, where Ar₁, Ar₂, R₃, X,and m are defined above for the Pyridylene Compounds of formula (I).

In one embodiment, Ar₁ is a pyridyl group;

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, m is 3.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, o is 2.

In another embodiment, o is 3.

In another embodiment, o is 4.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, q is 3.

In another embodiment, q is 4.

In another embodiment, q is 5.

In another embodiment, q is 6.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, r is 2

In another embodiment, r is 3

In another embodiment, r is 4

In another embodiment, r is 5

In another embodiment, s is 0.

In another embodiment, s is 1.

In another embodiment, s is 2.

In another embodiment, s is 3.

In another embodiment, s is 4.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —Br.

In another embodiment, R₁ is —I.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, n or p is 1 and R₂ is -halo, —OH, —NH₂, —CN, or—NO₂.

In another embodiment, n or p is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n or p is 1 and R₂ is -phenyl, -naphthyl,—(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₁₋₅—C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —(C₁-C_(1n))alkyl.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is -halo.

In another embodiment, m is 1 and R₃ is —Cl.

In another embodiment, m is 1 and R₃ is —Br.

In another embodiment, m is 1 and R₃ is —I.

In another embodiment, m is 1 and R₃ is —F.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, Ar₂ is a benzothiazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is a benzoimidazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is a benzooxazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

o is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

o is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

r is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

q is 1, and R₁₁ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

r is 1, and R₈ is at the para-position of the phenyl ring.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1, the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1, the —(C₁-C₆)alkyl is a tert-butyl group. Inanother embodiment, r is 1, the —(C₁-C₆)alkyl is a tert-butyl group andis substituted at the phenyl group's para-position. In anotherembodiment, r is 1, the —(C₁-C₆)alkyl is an iso-propyl group. In anotherembodiment, the —(C₁-C₆)alkyl is a iso-propyl group and is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is —CF₃. In another embodiment, r is 1 and the —CF₃ issubstituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1, the —(C₁-C₆)alkyl is a tert-butyl group,and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1, the —(C₁-C₆)alkyl is a iso-propyl group andis substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1, -halo is —I and is substituted at the phenyl group's para-position.In another embodiment, r is 1 and -halo is —F. In another embodiment, ris 1, -halo is —F and is substituted at the phenyl group'spara-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar_(t) is a pyridazinyl group, X is O, m is 0,Ar₂ is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

4.2 Pyridylene Compounds of Formula (II)

The invention also relates to Pyridylene Compounds of formula (II)

and pharmaceutically acceptable salts thereof, where Ar₁, Ar₂, X, R₃,and m are defined above for the Pyridylene Compounds of formula (II).

In one embodiment, Ar₁ is a pyridyl group;

In another embodiment, pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, m is 3.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, o is 2.

In another embodiment, o is 3.

In another embodiment, o is 4.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, q is 3.

In another embodiment, q is 4.

In another embodiment, q is 5.

In another embodiment, q is 6.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, r is 2

In another embodiment, r is 3

In another embodiment, r is 4

In another embodiment, r is 5

In another embodiment, s is 0.

In another embodiment, s is 1.

In another embodiment, s is 2.

In another embodiment, s is 3.

In another embodiment, s is 4.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —Br.

In another embodiment, R₁ is —I.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, n or p is 1 and R₂ is -halo, —OH, —NH₂, —CN, or—NO₂.

In another embodiment, n or p is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n or p is 1 and R₂ is -phenyl, -naphthyl,—(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂.

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, m is 1 and R₃ is -halo.

In another embodiment, m is 1 and R₃ is —Cl.

In another embodiment, m is 1 and R₃ is —Br.

In another embodiment, m is 1 and R₃ is —I.

In another embodiment, m is 1 and R₃ is —F.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, Ar₂ is a benzothiazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is a benzoimidazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is a benzooxazolyl group, s is 1, and R₈ is-halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

o is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

o is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

r is 1, and R₈ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

q is 1, and R₁₁ is -halo or —(C₁-C₆) alkyl.

In another embodiment, Ar₂ is

r is 1, and R₈ is at the para-position of the phenyl ring.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment,

r is 1 and the —(C₁-C₆)alkyl is a iso-propyl group and is substituted atthe phenyl group's para-position.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, Ar₂ is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupsubstituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is a —(C₁-C₆)alkyl. In another embodiment, r is 1 and the—(C₁-C₆)alkyl is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butyl group.In another embodiment, r is 1 and the —(C₁-C₆)alkyl is a tert-butylgroup and is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and the —(C₁-C₆)alkyl is an iso-propyl group. Inanother embodiment, r is 1 and the —(C₁-C₆)alkyl is a iso-propyl groupand is substituted at the phenyl group's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is —CF₃. In another embodiment, the —CF₃ is substitutedat the phenyl group's para-position.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, Ar₂is

r is 1, and R₈ is -halo. In another embodiment, r is 1 and the -halo issubstituted at the phenyl group's para-position. In another embodiment,r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cland is substituted at the phenyl group's para-position. In anotherembodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and-halo is —Br and is substituted at the phenyl group's para-position. Inanother embodiment, r is 1 and -halo is —I. In another embodiment, r is1 and -halo is —I and is substituted at the phenyl group'spara-position. In another embodiment, r is 1 and -halo is —F. In anotherembodiment, r is 1 and -halo is —F and is substituted at the phenylgroup's para-position.

4.3 Pyridylene Compounds of Formula (I) and (II)

In the Pyridylene Compounds that have an R₃ group, the R₃ group can beattached to the carbon atom at the 3-, 4-, or 6-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inone embodiment, the R₃ group is attached to the carbon at the 3-positionof the pyridylene ring of the Pyridylene Compound of formula (I) or(II). In another embodiment, the R₃ group is attached to the carbon atthe 4-position of the pyridylene ring of the Pyridylene Compound offormula (I) or (II). In another embodiment, the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

In another embodiment, the R₃ group is —CH₃ and the R₃ group is attachedto the carbon at the 3-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II). In another embodiment, the R₃ group is—CH₃ and the R₃ group is attached to the carbon at the 4-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inanother embodiment, the R₃ group is —CH₃ and the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

In another embodiment, the R₃ group is -halo and the R₃ group isattached to the carbon at the 3-position of the pyridylene ring of thePyridylene Compound of formula (I) or (II). In another embodiment, theR₃ group is -halo and the R₃ group is attached to the carbon at the4-position of the pyridylene ring of the Pyridylene Compound of formula(I) or (II). In another embodiment, the R₃ group is -halo and the R₃group is attached to the carbon at the 6-position of the pyridylene ringof the Pyridylene Compound of formula (I) or (II).

In another embodiment, the R₃ group is —Cl and the R₃ group is attachedto the carbon at the 3-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II). In another embodiment, the R₃ group is—Cl and the R₃ group is attached to the carbon at the 4-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inanother embodiment, the R₃ group is —Cl and the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

In another embodiment, the R₃ group is —Br and the R₃ group is attachedto the carbon at the 3-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II). In another embodiment, the R₃ group is—Br and the R₃ group is attached to the carbon at the 4-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inanother embodiment, the R₃ group is —Br and the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

In another embodiment, the R₃ group is —F and the R₃ group is attachedto the carbon at the 3-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II). In another embodiment, the R₃ group is—F and the R₃ group is attached to the carbon at the 4-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inanother embodiment, the R₃ group is —F and the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

In another embodiment, the R₃ group is —I and the R₃ group is attachedto the carbon at the 3-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II). In another embodiment, the R₃ group is—I and the R₃ group is attached to the carbon at the 4-position of thepyridylene ring of the Pyridylene Compound of formula (I) or (II). Inanother embodiment, the R₃ group is —I and the R₃ group is attached tothe carbon at the 6-position of the pyridylene ring of the PyridyleneCompound of formula (I) or (II).

Optical isomers of the Pyridylene Compounds can be obtained by knowntechniques such as chiral chromatography or formation of diastereomericsalts from an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of a PyridyleneCompound can be replaced by an isotope of the hydrogen, carbon or otheratoms. Such compounds, which are encompassed by the present invention,are useful as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays.

Illustrative Pyridylene Compounds are listed below in Tables 1-10.

For the chemical structure depicted, e.g., at the head of each of Tables1-5, a is independently 0 or 1. When a=0, the group at the “a” positionis —H. When a=1, the group at the “a” position (R_(8a)) is other than—H, i.e., is R₈.

For the chemical structure depicted, e.g., at the head of each of Tables6-10, a is independently 0 or 1. When a=0, the group at the “a” positionis —H. When a=1, the group at the “a” position ((R₈)_(a)) is other than—H, i.e., is R₈.

For the chemical structure depicted, e.g., at the head of each of Tables6-10, b is independently 0 or 1. When b=0, the group at the “b” positionis —H. When b=1, the group at the “b” position ((R₈)_(b)) is other than—H, i.e., is R₈.

TABLE 1 (III)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R_(8a)A1(a and b) —Cl —H A2(a and b) —Cl -tert-butyl A3(a and b) —Cl-iso-butyl A4(a and b) —Cl -sec-butyl A5(a and b) —Cl -iso-propyl A6(aand b) —Cl -n-propyl A7(a and b) —Cl -cyclohexyl A8(a and b) —Cl-tert-butoxy A9(a and b) —Cl -iso-propoxy A10(a and b) —Cl —CF₃ A11(aand b) —Cl —OCF₃ A12(a and b) —Cl —Cl A13(a and b) —Cl —Br A14(a and b)—Cl —I A15(a and b) —Cl -n-butyl A16(a and b) —Cl -n-propyl A17(a and b)—F —H A18(a and b) —F -tert-butyl A19(a and b) —F -iso-butyl A20(a andb) —F -sec-butyl A21(a and b) —F -iso-propyl A22(a and b) —F -n-propylA23(a and b) —F -cyclohexyl A24(a and b) —F -tert-butoxy A25(a and b) —F-iso-propoxy A26(a and b) —F —CF₃ A27(a and b) —F —OCF₃ A28(a and b) —F—Cl A29(a and b) —F —Br A30(a and b) —F —I A31(a and b) —F -n-butylA32(a and b) —F -n-propyl A33(a and b) —CH₃ —H A34(a and b) —CH₃-iso-butyl A35(a and b) —CH₃ -tert-butyl A36(a and b) —CH₃ -sec-butylA37(a and b) —CH₃ -iso-propyl A38(a and b) —CH₃ -n-propyl A39(a and b)—CH₃ -cyclohexyl A40(a and b) —CH₃ -tert-butoxy A41(a and b) —CH₃-iso-propoxy A42(a and b) —CH₃ —CF₃ A43(a and b) —CH₃ —OCF₃ A44(a and b)—CH₃ —Cl A45(a and b) —CH₃ —Br A46(a and b) —CH₃ —I A47(a and b) —CH₃-n-butyl A48(a and b) —CH₃ -n-propyl A49(a and b) —CF₃ —H A50(a and b)—CF₃ -tert-butyl A51(a and b) —CF₃ -iso-butyl A52(a and b) —CF₃-sec-butyl A53(a and b) —CF₃ -iso-propyl A54(a and b) —CF₃ -n-propylA55(a and b) —CF₃ -cyclohexyl A56(a and b) —CF₃ -tert-butoxy A57(a andb) —CF₃ -iso-propoxy A58(a and b) —CF₃ —CF₃ A59(a and b) —CF₃ —OCF₃A60(a and b) —CF₃ —Cl A61(a and b) —CF₃ —Br A62(a and b) —CF₃ —I A63(aand b) —CF₃ -n-butyl A64(a and b) —CF₃ -n-propyl A65(a and b) —CHF₂-tert-butyl A66(a and b) —CHF₂ —H A67(a and b) —CHF₂ -iso-butyl A68(aand b) —CHF₂ -sec-butyl A69(a and b) —CHF₂ -iso-propyl A70(a and b)—CHF₂ -n-propyl A71(a and b) —CHF₂ -cyclohexyl A72(a and b) —CHF₂-tert-butoxy A73(a and b) —CHF₂ -iso-propoxy A74(a and b) —CHF₂ —CF₃A75(a and b) —CHF₂ —OCF₃ A76(a and b) —CHF₂ —Cl A77(a and b) —CHF₂ —BrA78(a and b) —CHF₂ —I A79(a and b) —CHF₂ -n-butyl A80(a and b) —CHF₂-n-propyl A81(a and b) —Br —H A82(a and b) —Br -tert-butyl A83(a and b)—Br -iso-butyl A84(a and b) —Br -sec-butyl A85(a and b) —Br -iso-propylA86(a and b) —Br -n-propyl A87(a and b) —Br -cyclohexyl A88(a and b) —Br-tert-butoxy A89(a and b) —Br -iso-propoxy A90(a and b) —Br —CF₃ A91(aand b) —Br —OCF₃ A92(a and b) —Br —Cl A93(a and b) —Br —Br A94(a and b)—Br —I A95(a and b) —Br -n-butyl A96(a and b) —Br -n-propyl A97(a and b)—I -tert-butyl A98(a and b) —I —H A99(a and b) —I -iso-butyl A100(a andb) —I -sec-butyl A101(a and b) —I -iso-propyl A102(a and b) —I -n-propylA103(a and b) —I -cyclohexyl A104(a and b) —I -tert-butoxy A105(a and b)—I -iso-propoxy A106(a and b) —I —CF₃ A107(a and b) —I —OCF₃ A108(a andb) —I —Cl A109(a and b) —I —Br A110(a and b) —I —I A111(a and b) —I-n-butyl A112(a and b) —I -n-propyl In the column labeled “Compound”:(a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 2 (IV)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R_(8a)B1(a and b) —Cl —H B2(a and b) —Cl -tert-butyl B3(a and b) —Cl-iso-butyl B4(a and b) —Cl -sec-butyl B5(a and b) —Cl -iso-propyl B6(aand b) —Cl -n-propyl B7(a and b) —Cl -cyclohexyl B8(a and b) —Cl-tert-butoxy B9(a and b) —Cl -iso-propoxy B10(a and b) —Cl —CF₃ B11(aand b) —Cl —OCF₃ B12(a and b) —Cl —Cl B13(a and b) —Cl —Br B14(a and b)—Cl —I B15(a and b) —Cl -n-butyl B16(a and b) —Cl -n-propyl B17(a and b)—F —H B18(a and b) —F -tert-butyl B19(a and b) —F -iso-butyl B20(a andb) —F -sec-butyl B21(a and b) —F -iso-propyl B22(a and b) —F -n-propylB23(a and b) —F -cyclohexyl B24(a and b) —F -tert-butoxy B25(a and b) —F-iso-propoxy B26(a and b) —F —CF₃ B27(a and b) —F —OCF₃ B28(a and b) —F—Cl B29(a and b) —F —Br B30(a and b) —F —I B31(a and b) —F -n-butylB32(a and b) —F -n-propyl B33(a and b) —CH₃ —H B34(a and b) —CH₃-iso-butyl B35(a and b) —CH₃ -tert-butyl B36(a and b) —CH₃ -sec-butylB37(a and b) —CH₃ -iso-propyl B38(a and b) —CH₃ -n-propyl B39(a and b)—CH₃ -cyclohexyl B40(a and b) —CH₃ -tert-butoxy B41(a and b) —CH₃-iso-propoxy B42(a and b) —CH₃ —CF₃ B43(a and b) —CH₃ —OCF₃ B44(a and b)—CH₃ —Cl B45(a and b) —CH₃ —Br B46(a and b) —CH₃ —I B47(a and b) —CH₃-n-butyl B48(a and b) —CH₃ -n-propyl B49(a and b) —CF₃ —H B50(a and b)—CF₃ -tert-butyl B51(a and b) —CF₃ -iso-butyl B52(a and b) —CF₃-sec-butyl B53(a and b) —CF₃ -iso-propyl B54(a and b) —CF₃ -n-propylB55(a and b) —CF₃ -cyclohexyl B56(a and b) —CF₃ -tert-butoxy B57(a andb) —CF₃ -iso-propoxy B58(a and b) —CF₃ —CF₃ B59(a and b) —CF₃ —OCF₃B60(a and b) —CF₃ —Cl B61(a and b) —CF₃ —Br B62(a and b) —CF₃ —I B63(aand b) —CF₃ -n-butyl B64(a and b) —CF₃ -n-propyl B65(a and b) —CHF₂-tert-butyl B66(a and b) —CHF₂ —H B67(a and b) —CHF₂ -iso-butyl B68(aand b) —CHF₂ -sec-butyl B69(a and b) —CHF₂ -iso-propyl B70(a and b)—CHF₂ -n-propyl B71(a and b) —CHF₂ -cyclohexyl B72(a and b) —CHF₂-tert-butoxy B73(a and b) —CHF₂ -iso-propoxy B74(a and b) —CHF₂ —CF₃B75(a and b) —CHF₂ —OCF₃ B76(a and b) —CHF₂ —Cl B77(a and b) —CHF₂ —BrB78(a and b) —CHF₂ —I B79(a and b) —CHF₂ -n-butyl B80(a and b) —CHF₂-n-propyl B81(a and b) —Br —H B82(a and b) —Br -tert-butyl B83(a and b)—Br -iso-butyl B84(a and b) —Br -sec-butyl B85(a and b) —Br -iso-propylB86(a and b) —Br -n-propyl B87(a and b) —Br -cyclohexyl B88(a and b) —Br-tert-butoxy B89(a and b) —Br -iso-propoxy B90(a and b) —Br —CF₃ B91(aand b) —Br —OCF₃ B92(a and b) —Br —Cl B93(a and b) —Br —Br B94(a and b)—Br —I B95(a and b) —Br -n-butyl B96(a and b) —Br -n-propyl B97(a and b)—I -tert-butyl B98(a and b) —I —H B99(a and b) —I -iso-butyl B100(a andb) —I -sec-butyl B101(a and b) —I -iso-propyl B102(a and b) —I -n-propylB103(a and b) —I -cyclohexyl B104(a and b) —I -tert-butoxy B105(a and b)—I -iso-propoxy B106(a and b) —I —CF₃ B107(a and b) —I —OCF₃ B108(a andb) —I —Cl B109(a and b) —I —Br B110(a and b) —I —I B111(a and b) —I-n-butyl B112(a and b) —I -n-propyl In the column labeled “Compound”:(a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 3 (V)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R_(8a)C1(a and b) —Cl —H C2(a and b) —Cl -tert-butyl C3(a and b) —Cl-iso-butyl C4(a and b) —Cl -sec-butyl C5(a and b) —Cl -iso-propyl C6(aand b) —Cl -n-propyl C7(a and b) —Cl -cyclohexyl C8(a and b) —Cl-tert-butoxy C9(a and b) —Cl -iso-propoxy C10(a and b) —Cl —CF₃ C11(aand b) —Cl —OCF₃ C12(a and b) —Cl —Cl C13(a and b) —Cl —Br C14(a and b)—Cl —I C15(a and b) —Cl -n-butyl C16(a and b) —Cl -n-propyl C17(a and b)—F —H C18(a and b) —F -tert-butyl C19(a and b) —F -iso-butyl C20(a andb) —F -sec-butyl C21(a and b) —F -iso-propyl C22(a and b) —F -n-propylC23(a and b) —F -cyclohexyl C24(a and b) —F -tert-butoxy C25(a and b) —F-iso-propoxy C26(a and b) —F —CF₃ C27(a and b) —F —OCF₃ C28(a and b) —F—Cl C29(a and b) —F —Br C30(a and b) —F —I C31(a and b) —F -n-butylC32(a and b) —F -n-propyl C33(a and b) —CH₃ —H C34(a and b) —CH₃-iso-butyl C35(a and b) —CH₃ -tert-butyl C36(a and b) —CH₃ -sec-butylC37(a and b) —CH₃ -iso-propyl C38(a and b) —CH₃ -n-propyl C39(a and b)—CH₃ -cyclohexyl C40(a and b) —CH₃ -tert-butoxy C41(a and b) —CH₃-iso-propoxy C42(a and b) —CH₃ —CF₃ C43(a and b) —CH₃ —OCF₃ C44(a and b)—CH₃ —Cl C45(a and b) —CH₃ —Br C46(a and b) —CH₃ —I C47(a and b) —CH₃-n-butyl C48(a and b) —CH₃ -n-propyl C49(a and b) —CF₃ —H C50(a and b)—CF₃ -tert-butyl C51(a and b) —CF₃ -iso-butyl C52(a and b) —CF₃-sec-butyl C53(a and b) —CF₃ -iso-propyl C54(a and b) —CF₃ -n-propylC55(a and b) —CF₃ -cyclohexyl C56(a and b) —CF₃ -tert-butoxy C57(a andb) —CF₃ -iso-propoxy C58(a and b) —CF₃ —CF₃ C59(a and b) —CF₃ —OCF₃C60(a and b) —CF₃ —Cl C61(a and b) —CF₃ —Br C62(a and b) —CF₃ —I C63(aand b) —CF₃ -n-butyl C64(a and b) —CF₃ -n-propyl C65(a and b) —CHF₂-tert-butyl C66(a and b) —CHF₂ —H C67(a and b) —CHF₂ -iso-butyl C68(aand b) —CHF₂ -sec-butyl C69(a and b) —CHF₂ -iso-propyl C70(a and b)—CHF₂ -n-propyl C71(a and b) —CHF₂ -cyclohexyl C72(a and b) —CHF₂-tert-butoxy C73(a and b) —CHF₂ -iso-propoxy C74(a and b) —CHF₂ —CF₃C75(a and b) —CHF₂ —OCF₃ C76(a and b) —CHF₂ —Cl C77(a and b) —CHF₂ —BrC78(a and b) —CHF₂ —I C79(a and b) —CHF₂ -n-butyl C80(a and b) —CHF₂-n-propyl C81(a and b) —Br —H C82(a and b) —Br -tert-butyl C83(a and b)—Br -iso-butyl C84(a and b) —Br -sec-butyl C85(a and b) —Br -iso-propylC86(a and b) —Br -n-propyl C87(a and b) —Br -cyclohexyl C88(a and b) —Br-tert-butoxy C89(a and b) —Br -iso-propoxy C90(a and b) —Br —CF₃ C91(aand b) —Br —OCF₃ C92(a and b) —Br —Cl C93(a and b) —Br —Br C94(a and b)—Br —I C95(a and b) —Br -n-butyl C96(a and b) —Br -n-propyl C97(a and b)—I -tert-butyl C98(a and b) —I —H C99(a and b) —I -iso-butyl C100(a andb) —I -sec-butyl C101(a and b) —I -iso-propyl C102(a and b) —I -n-propylC103(a and b) —I -cyclohexyl C104(a and b) —I -tert-butoxy C105(a and b)—I -iso-propoxy C106(a and b) —I —CF₃ C107(a and b) —I —OCF₃ C108(a andb) —I —Cl C109(a and b) —I —Br C110(a and b) —I —I C111(a and b) —I-n-butyl C112(a and b) —I -n-propyl In the column labeled “Compound”:(a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 4 (VI)

Compound R₁ R_(8a) D1(a and b) —Cl —H D2(a and b) —Cl -tert-butyl D3(aand b) —Cl -iso-butyl D4(a and b) —Cl -sec-butyl D5(a and b) —Cl-iso-propyl D6(a and b) —Cl -n-propyl D7(a and b) —Cl -cyclohexyl D8(aand b) —Cl -tert-butoxy D9(a and b) —Cl -iso-propoxy D10(a and b) —Cl—CF₃ D11(a and b) —Cl —OCF₃ D12(a and b) —Cl —Cl D13( a and b) —Cl —BrD14( a and b) —Cl —I D15(a and b) —Cl -n-butyl D16(a and b) —Cl-n-propyl D17(a and b) —F —H D18(a and b) —F -tert-butyl D19(a and b) —F-iso-butyl D20(a and b) —F -sec-butyl D21(a and b) —F -iso-propyl D22(aand b) —F -n-propyl D23(a and b) —F -cyclohexyl D24(a and b) —F-tert-butoxy D25(a and b) —F -iso-propoxy D26(a and b) —F —CF₃ D27(a andb) —F —OCF₃ D28(a and b) —F —Cl D29(a and b) —F —Br D30(a and b) —F —ID31(a and b) —F -n-butyl D32(a and b) —F -n-propyl D33(a and b) —CH₃ —HD34(a and b) —CH₃ -iso-butyl D35(a and b) —CH₃ -tert-butyl D36(a and b)—CH₃ -sec-butyl D37(a and b) —CH₃ -iso-propyl D38(a and b) —CH₃-n-propyl D39(a and b) —CH₃ -cyclohexyl D40(a and b) —CH₃ -tert-butoxyD41(a and b) —CH₃ -iso-propoxy D42(a and b) —CH₃ —CF₃ D43(a and b) —CH₃—OCF₃ D44(a and b) —CH₃ —Cl D45(a and b) —CH₃ —Br D46(a and b) —CH₃ —ID47(a and b) —CH₃ -n-butyl D48(a and b) —CH₃ -n-propyl D49(a and b) —CF₃—H D50(a and b) —CF₃ -tert-butyl D51(a and b) —CF₃ -iso-butyl D52(a andb) —CF₃ -sec-butyl D53(a and b) —CF₃ -iso-propyl D54(a and b) —CF₃-n-propyl D55(a and b) —CF₃ -cyclohexyl D56(a and b) —CF₃ -tert-butoxyD57(a and b) —CF₃ -iso-propoxy D58(a and b) —CF₃ —CF₃ D59(a and b) —CF₃—OCF₃ D60(a and b) —CF₃ —Cl D61(a and b) —CF₃ —Br D62(a and b) —CF₃ —ID63(a and b) —CF₃ -n-butyl D64(a and b) —CF₃ -n-propyl D65(a and b)—CHF₂ -tert-butyl D66(a and b) —CHF₂ —H D67(a and b) —CHF₂ -iso-butylD68(a and b) —CHF₂ -sec-butyl D69(a and b) —CHF₂ -iso-propyl D70(a andb) —CHF₂ -n-propyl D71(a and b) —CHF₂ -cyclohexyl D72(a and b) —CHF₂-tert-butoxy D73(a and b) —CHF₂ -iso-propoxy D74(a and b) —CHF₂ —CF₃D75(a and b) —CHF₂ —OCF₃ D76(a and b) —CHF₂ —Cl D77(a and b) —CHF₂ —BrD78(a and b) —CHF₂ —I D79(a and b) —CHF₂ -n-butyl D80(a and b) —CHF₂-n-propyl D81(a and b) —Br —H D82(a and b) —Br -tert-butyl D83(a and b)—Br -iso-butyl D84(a and b) —Br -sec-butyl D85(a and b) —Br -iso-propylD86(a and b) —Br -n-propyl D87(a and b) —Br -cyclohexyl D88(a and b) —Br-tert-butoxy D89(a and b) —Br -iso-propoxy D90(a and b) —Br —CF₃ D91(aand b) —Br —OCF₃ D92(a and b) —Br —Cl D93(a and b) —Br —Br D94(a and b)—Br —I D95(a and b) —Br -n-butyl D96(a and b) —Br -n-propyl D97(a and b)—I -tert-butyl D98(a and b) —I —H D99(a and b) —I -iso-butyl D100(a andb) —I -sec-butyl D101(a and b) —I -iso-propyl D102(a and b) —I -n-propylD103(a and b) —I -cyclohexyl D104(a and b) —I -tert-butoxy D105(a and b)—I -iso-propoxy D106(a and b) —I —CF₃ D107(a and b) —I —OCF₃ D108(a andb) —I —Cl D109(a and b) —I —Br D110(a and b) —I —I D111(a and b) —I-n-butyl D112(a and b) —I -n-propyl In the column labeled “Compound”:(a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 5 (VII)

Compound R₁ R_(8a) E1(a and b) —Cl —H E2(a and b) —Cl -tert-butyl E3(aand b) —Cl -iso-butyl E4(a and b) —Cl -sec-butyl E5(a and b) —Cl-iso-propyl E6(a and b) —Cl -n-propyl E7(a and b) —Cl -cyclohexyl E8(aand b) —Cl -tert-butoxy E9(a and b) —Cl -iso-propoxy E10(a and b) —Cl—CF₃ E11(a and b) —Cl —OCF₃ E12(a and b) —Cl —Cl E13(a and b) —Cl —BrE14(a and b) —Cl —I E15(a and b) —Cl -n-butyl E16(a and b) —Cl -n-propylE17(a and b) —F —H E18(a and b) —F -tert-butyl E19(a and b) —F-iso-butyl E20(a and b) —F -sec-butyl E21(a and b) —F -iso-propyl E22(aand b) —F -n-propyl E23(a and b) —F -cyclohexyl E24(a and b) —F-tert-butoxy E25(a and b) —F -iso-propoxy E26(a and b) —F —CF₃ E27(a andb) —F —OCF₃ E28(a and b) —F —Cl E29(a and b) —F —Br E30(a and b) —F —IE31(a and b) —F -n-butyl E32(a and b) —F -n-propyl E33(a and b) —CH₃ —HE34(a and b) —CH₃ -iso-butyl E35(a and b) —CH₃ -tert-butyl E36(a and b)—CH₃ -sec-butyl E37(a and b) —CH₃ -iso-propyl E38(a and b) —CH₃-n-propyl E39(a and b) —CH₃ -cyclohexyl E40(a and b) —CH₃ -tert-butoxyE41(a and b) —CH₃ -iso-propoxy E42(a and b) —CH₃ —CF₃ E43(a and b) —CH₃—OCF₃ E44(a and b) —CH₃ —Cl E45(a and b) —CH₃ —Br E46(a and b) —CH₃ —IE47(a and b) —CH₃ -n-butyl E48(a and b) —CH₃ -n-propyl E49(a and b) —CF₃—H E50(a and b) —CF₃ -tert-butyl E51(a and b) —CF₃ -iso-butyl E52(a andb) —CF₃ -sec-butyl E53(a and b) —CF₃ -iso-propyl E54(a and b) —CF₃-n-propyl E55(a and b) —CF₃ -cyclohexyl E56(a and b) —CF₃ -tert-butoxyE57(a and b) —CF₃ -iso-propoxy E58(a and b) —CF₃ —CF₃ E59(a and b) —CF₃—OCF₃ E60(a and b) —CF₃ —Cl E61(a and b) —CF₃ —Br E62(a and b) —CF₃ —IE63(a and b) —CF₃ -n-butyl E64(a and b) —CF₃ -n-propyl E65(a and b)—CHF₂ -tert-butyl E66(a and b) —CHF₂ —H E67(a and b) —CHF₂ -iso-butylE68(a and b) —CHF₂ -sec-butyl E69(a and b) —CHF₂ -iso-propyl E70(a andb) —CHF₂ -n-propyl E71(a and b) —CHF₂ -cyclohexyl E72(a and b) —CHF₂-tert-butoxy E73(a and b) —CHF₂ -iso-propoxy E74(a and b) —CHF₂ —CF₃E75(a and b) —CHF₂ —OCF₃ E76(a and b) —CHF₂ —Cl E77(a and b) —CHF₂ —BrE78(a and b) —CHF₂ —I E79(a and b) —CHF₂ -n-butyl E80(a and b) —CHF₂-n-propyl E81(a and b) —Br —H E82(a and b) —Br -tert-butyl E83(a and b)—Br -iso-butyl E84(a and b) —Br -sec-butyl E85(a and b) —Br -iso-propylE86(a and b) —Br -n-propyl E87(a and b) —Br -cyclohexyl E88(a and b) —Br-tert-butoxy E89(a and b) —Br -iso-propoxy E90(a and b) —Br —CF₃ E91(aand b) —Br —OCF₃ E92(a and b) —Br —Cl E93(a and b) —Br —Br E94(a and b)—Br —I E95(a and b) —Br -n-butyl E96(a and b) —Br -n-propyl E97(a and b)—I -tert-butyl E98(a and b) —I —H E99(a and b) —I -iso-butyl E100(a andb) —I -sec-butyl E101(a and b) —I -iso-propyl E102(a and b) —I -n-propylE103(a and b) —I -cyclohexyl E104(a and b) —I -tert-butoxy E105(a and b)—I -iso-propoxy E106(a and b) —I —CF₃ E107(a and b) —I —OCF₃ E108(a andb) —I —Cl E109(a and b) —I —Br E110(a and b) —I —I E111(a and b) —I-n-butyl E112(a and b) —I -n-propyl In the column labeled “Compound”:(a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 6 (VIII)

Compound Y R₁ (R₈)_(a) (R₈)_(b) F1(a and b) S —Cl —Cl —H F2(a and b) S—Cl —Br —H F3(a and b) S —Cl —F —H F4(a and b) S —Cl —CH₃ —H F5(a and b)S —Cl —CF₃ —H F6(a and b) S —Cl —OCH₃ —H F7(a and b) S —Cl —OCH₂CH₃ —HF8(a and b) S —Cl —OCF₃ —H F9(a and b) S —Cl -tert-butyl —H F10(a and b)S —Cl -iso-propyl —H F11(a and b) S —Cl —CH₃ —CH₃ F12(a and b) S —Cl —H—H F13(a and b) S —Cl —H —Cl F14(a and b) S —Cl —H —Br F15(a and b) S—Cl —H —F F16(a and b) S —Cl —H —CH₃ F17(a and b) S —Cl —H —CF₃ F18(aand b) S —Cl —H —OCH₃ F19(a and b) S —Cl —H —OCH₂CH₃ F20(a and b) S —Cl—H —OCF₃ F21(a and b) S —Cl —H -tert-butyl F22(a and b) S —Cl —H-iso-propyl F23(a and b) S —CH₃ —Cl —H F24(a and b) S —CH₃ —Br —H F25(aand b) S —CH₃ —F —H F26(a and b) S —CH₃ —CH₃ —H F27(a and b) S —CH₃ —CF₃—H F28(a and b) S —CH₃ —OCH₃ —H F29(a and b) S —CH₃ —OCH₂CH₃ —H F30(aand b) S —CH₃ —OCF₃ —H F31(a and b) S —CH₃ -tert-butyl —H F32(a and b) S—CH₃ -iso-propyl —H F33(a and b) S —CH₃ —CH₃ —CH₃ F34(a and b) S —CH₃ —H—H F35(a and b) S —CH₃ —H —Cl F36(a and b) S —CH₃ —H —Br F37(a and b) S—CH₃ —H —F F38(a and b) S —CH₃ —H —CH₃ F39(a and b) S —CH₃ —H —CF₃ F40(aand b) S —CH₃ —H —OCH₃ F41(a and b) S —CH₃ —H —OCH₂CH₃ F42(a and b) S—CH₃ —H —OCF₃ F43(a and b) S —CH₃ —H -tert-butyl F44(a and b) S —CH₃ —H-iso-propyl F45(a and b) S —CF₃ —Cl —H F46(a and b) S —CF₃ —Br —H F47(aand b) S —CF₃ —F —H F48(a and b) S —CF₃ —CH₃ —H F49(a and b) S —CF₃ —CF₃—H F50(a and b) S —CF₃ —OCH₃ —H F51(a and b) S —CF₃ —OCH₂CH₃ —H F52(aand b) S —CF₃ —OCF₃ —H F53(a and b) S —CF₃ -tert-butyl —H F54(a and b) S—CF₃ -iso-propyl —H F55(a and b) S —CF₃ —CH₃ —CH₃ F56(a and b) S —CF₃ —H—H F57(a and b) S —CF₃ —H —Cl F58(a and b) S —CF₃ —H —Br F59(a and b) S—CF₃ —H —F F60(a and b) S —CF₃ —H —CH₃ F61(a and b) S —CF₃ —H —CF₃ F62(aand b) S —CF₃ —H —OCH₃ F63(a and b) S —CF₃ —H —OCH₂CH₃ F64(a and b) S—CF₃ —H —OCF₃ F65(a and b) S —CF₃ —H -tert-butyl F66(a and b) S —CF₃ —H-iso-propyl F67(a and b) S —CHF₂ —Cl —H F68(a and b) S —CHF₂ —Br —HF69(a and b) S —CHF₂ —F —H F70(a and b) S —CHF₂ —CH₃ —H F71(a and b) S—CHF₂ —CF₃ —H F72(a and b) S —CHF₂ —OCH₃ —H F73(a and b) S —CHF₂—OCH₂CH₃ —H F74(a and b) S —CHF₂ —OCF₃ —H F75(a and b) S —CHF₂-tert-butyl —H F76(a and b) S —CHF₂ -iso-propyl —H F77(a and b) S —CHF₂—CH₃ —CH₃ F78(a and b) S —CHF₂ —H —H F79(a and b) S —CHF₂ —H —Cl F80(aand b) S —CHF₂ —H —Br F81(a and b) S —CHF₂ —H —F F82(a and b) S —CHF₂ —H—CH₃ F83(a and b) S —CHF₂ —H —CF₃ F84(a and b) S —CHF₂ —H —OCH₃ F85(aand b) S —CHF₂ —H —OCH₂CH₃ F86(a and b) S —CHF₂ —H —OCF₃ F87(a and b) S—CHF₂ —H -tert-butyl F88(a and b) S —CHF₂ —H -iso-propyl F89(a and b) S—Br —Br —H F90(a and b) S —Br —Cl —H F91(a and b) S —Br —F —H F92(a andb) S —Br —CH₃ —H F93(a and b) S —Br —CF₃ —H F94(a and b) S —Br —OCH₃ —HF95(a and b) S —Br —OCH₂CH₃ —H F96(a and b) S —Br —OCF₃ —H F97(a and b)S —Br -tert-butyl —H F98(a and b) S —Br -iso-propyl —H F99(a and b) S—Br —CH₃ —CH₃ F100(a and b) S —Br —H —H F101(a and b) S —Br —H —ClF102(a and b) S —Br —H —Br F103(a and b) S —Br —H —F F104(a and b) S —Br—H —CH₃ F105(a and b) S —Br —H —CF₃ F106(a and b) S —Br —H —OCH₃ F107(aand b) S —Br —H —OCH₂CH₃ F108(a and b) S —Br —H —OCF₃ F109(a and b) S—Br —H -tert-butyl F110(a and b) S —Br —H -iso-propyl F111(a and b) S —I—Cl —H F112(a and b) S —I —Br —H F113(a and b) S —I —F —H F114(a and b)S —I —CH₃ —H F115(a and b) S —I —CF₃ —H F116(a and b) S —I —OCH₃ —HF117(a and b) S —I —OCH₂CH₃ —H F118(a and b) S —I —OCF₃ —H F119(a and b)S —I -tert-butyl —H F120(a and b) S —I -iso-propyl —H F121(a and b) S —I—CH₃ —CH₃ F122(a and b) S —I —H —H F123(a and b) S —I —H —Cl F124(a andb) S —I —H —Br F125(a and b) S —I —H —F F126(a and b) S —I —H —CH₃F127(a and b) S —I —H —CF₃ F128(a and b) S —I —H —OCH₃ F129(a and b) S—I —H —OCH₂CH₃ F130(a and b) S —I —H —OCF₃ F131(a and b) S —I —H-tert-butyl F132(a and b) S —I —H -iso-propyl F133(a and b) O —Cl —Cl —HF134(a and b) O —Cl —Br —H F135(a and b) O —Cl —F —H F136(a and b) O —Cl—CH₃ —H F137(a and b) O —Cl —CF₃ —H F138(a and b) O —Cl —OCH₃ —H F139(aand b) O —Cl —OCH₂CH₃ —H F140(a and b) O —Cl —OCF₃ —H F141(a and b) O—Cl -tert-butyl —H F142(a and b) O —Cl -iso-propyl —H F143(a and b) O—Cl —CH₃ —CH₃ F144(a and b) O —Cl —H —H F145(a and b) O —Cl —H —CH₃F146(a and b) O —Cl —H —Cl F147(a and b) O —Cl —H —Br F148(a and b) O—Cl —H —F F149(a and b) O —Cl —H —CF₃ F150(a and b) O —Cl —H —OCH₃F151(a and b) O —Cl —H —OCH₂CH₃ F152(a and b) O —Cl —H —OCF₃ F153(a andb) O —Cl —H -tert-butyl F154(a and b) O —Cl —H -iso-propyl F155(a and b)O —CH₃ —Cl —H F156(a and b) O —CH₃ —Br —H F157(a and b) O —CH₃ —F —HF158(a and b) O —CH₃ —CH₃ —H F159(a and b) O —CH₃ —CF₃ —H F160(a and b)O —CH₃ —OCH₃ —H F161(a and b) O —CH₃ —OCH₂CH₃ —H F162(a and b) O —CH₃—OCF₃ —H F163(a and b) O —CH₃ -tert-butyl —H F164(a and b) O —CH₃-iso-propyl —H F165(a and b) O —CH₃ —CH₃ —CH₃ F166(a and b) O —CH₃ —H —HF167(a and b) O —CH₃ —H —Cl F168(a and b) O —CH₃ —H —Br F169(a and b) O—CH₃ —H —F F170(a and b) O —CH₃ —H —CH₃ F171(a and b) O —CH₃ —H —CF₃F172(a and b) O —CH₃ —H —OCH₃ F173(a and b) O —CH₃ —H —OCH₂CH₃ F174(aand b) O —CH₃ —H —OCF₃ F175(a and b) O —CH₃ —H -tert-butyl F176(a and b)O —CH₃ —H -iso-propyl F177(a and b) O —CF₃ —Cl —H F178(a and b) O —CF₃—Br —H F179(a and b) O —CF₃ —F —H F180(a and b) O —CF₃ —CH₃ —H F181(aand b) O —CF₃ —CF₃ —H F182(a and b) O —CF₃ —OCH₃ —H F183(a and b) O —CF₃—OCH₂CH₃ —H F184(a and b) O —CF₃ —OCF₃ —H F185(a and b) O —CF₃-tert-butyl —H F186(a and b) O —CF₃ -iso-propyl —H F187(a and b) O —CF₃—CH₃ —CH₃ F188(a and b) O —CF₃ —H —H F189(a and b) O —CF₃ —H —Cl F190(aand b) O —CF₃ —H —Br F191(a and b) O —CF₃ —H —F F192(a and b) O —CF₃ —H—CH₃ F193(a and b) O —CF₃ —H —CF₃ F194(a and b) O —CF₃ —H —OCH₃ F195(aand b) O —CF₃ —H —OCH₂CH₃ F196(a and b) O —CF₃ —H —OCF₃ F197(a and b) O—CF₃ —H -tert-butyl F198(a and b) O —CF₃ —H -iso-propyl F199(a and b) O—CHF₂ —Cl —H F200(a and b) O —CHF₂ —Br —H F201(a and b) O —CHF₂ —F —HF202(a and b) O —CHF₂ —CH₃ —H F203(a and b) O —CHF₂ —CF₃ —H F204(a andb) O —CHF₂ —OCH₃ —H F205(a and b) O —CHF₂ —OCH₂CH₃ —H F206(a and b) O—CHF₂ —OCF₃ —H F207(a and b) O —CHF₂ -tert-butyl —H F208(a and b) O—CHF₂ -iso-propyl —H F209(a and b) O —CHF₂ —CH₃ —CH₃ F210(a and b) O—CHF₂ —H —H F211(a and b) O —CHF₂ —H —Cl F212(a and b) O —CHF₂ —H —BrF213(a and b) O —CHF₂ —H —F F214(a and b) O —CHF₂ —H —CH₃ F215(a and b)O —CHF₂ —H —CF₃ F216(a and b) O —CHF₂ —H —OCH₃ F217(a and b) O —CHF₂ —H—OCH₂CH₃ F218(a and b) O —CHF₂ —H —OCF₃ F219(a and b) O —CHF₂ —H-tert-butyl F220(a and b) O —CHF₂ —H -iso-propyl F221(a and b) O —Br —Br—H F222(a and b) O —Br —Cl —H F223(a and b) O —Br —F —H F224(a and b) O—Br —CH₃ —H F225(a and b) O —Br —CF₃ —H F226(a and b) O —Br —OCH₃ —HF227(a and b) O —Br —OCH₂CH₃ —H F228(a and b) O —Br —OCF₃ —H F229(a andb) O —Br -tert-butyl —H F230(a and b) O —Br -iso-propyl —H F231(a and b)O —Br —CH₃ —CH₃ F232(a and b) O —Br —H —H F233(a and b) O —Br —H —ClF234(a and b) O —Br —H —Br F235(a and b) O —Br —H —F F236(a and b) O —Br—H —CH₃ F237(a and b) O —Br —H —CF₃ F238(a and b) O —Br —H —OCH₃ F239(aand b) O —Br —H —OCH₂CH₃ F240(a and b) O —Br —H —OCF₃ F241(a and b) O—Br —H -tert-butyl F242(a and b) O —Br —H -iso-propyl F243(a and b) O —I—Cl —H F244(a and b) O —I —Br —H F245(a and b) O —I —F —H F246(a and b)O —I —CH₃ —H F247(a and b) O —I —CF₃ —H F248(a and b) O —I —OCH₃ —HF249(a and b) O —I —OCH₂CH₃ —H F250(a and b) O —I —OCF₃ —H F251(a and b)O —I -tert-butyl —H F252(a and b) O —I -iso-propyl —H F253(a and b) O —I—CH₃ —CH₃ F254(a and b) O —I —H —H F255(a and b) O —I —H —Cl F256(a andb) O —I —H —Br F257(a and b) O —I —H —F F258(a and b) O —I —H —CH₃F259(a and b) O —I —H —CF₃ F260(a and b) O —I —H —OCH₃ F261(a and b) O—I —H —OCH₂CH₃ F262(a and b) O —I —H —OCF₃ F263(a and b) O —I —H-tert-butyl F264(a and b) O —I —H -iso-propyl F265(a and b) NH —Cl —Cl—H F266(a and b) NH —Cl —Br —H F267(a and b) NH —Cl —F —H F268(a and b)NH —Cl —CH₃ —H F269(a and b) NH —Cl —CF₃ —H F270(a and b) NH —Cl —OCH₃—H F271(a and b) NH —Cl —OCH₂CH₃ —H F272(a and b) NH —Cl —OCF₃ —H F273(aand b) NH —Cl -tert-butyl —H F274(a and b) NH —Cl -iso-propyl —H F275(aand b) NH —Cl —CH₃ —CH₃ F276(a and b) NH —Cl —H —H F277(a and b) NH —Cl—H —CH₃ F278(a and b) NH —Cl —H —Cl F279(a and b) NH —Cl —H —Br F280(aand b) NH —Cl —H —F F281(a and b) NH —Cl —H —CF₃ F282(a and b) NH —Cl —H—OCH₃ F283(a and b) NH —Cl —H —OCH₂CH₃ F284(a and b) NH —Cl —H —OCF₃F285(a and b) NH —Cl —H -tert-butyl F286(a and b) NH —Cl —H -iso-propylF287(a and b) NH —CH₃ —Cl —H F288(a and b) NH —CH₃ —Br —H F289(a and b)NH —CH₃ —F —H F290(a and b) NH —CH₃ —CH₃ —H F291(a and b) NH —CH₃ —CF₃—H F292(a and b) NH —CH₃ —OCH₃ —H F293(a and b) NH —CH₃ —OCH₂CH₃ —HF294(a and b) NH —CH₃ —OCF₃ —H F295(a and b) NH —CH₃ -tert-butyl —HF296(a and b) NH —CH₃ -iso-propyl —H F297(a and b) NH —CH₃ —CH₃ —CH₃F298(a and b) NH —CH₃ —H —H F299(a and b) NH —CH₃ —H —Cl F300(a and b)NH —CH₃ —H —Br F301(a and b) NH —CH₃ —H —F F302(a and b) NH —CH₃ —H —CH₃F303(a and b) NH —CH₃ —H —CF₃ F304(a and b) NH —CH₃ —H —OCH₃ F305(a andb) NH —CH₃ —H —OCH₂CH₃ F306(a and b) NH —CH₃ —H —OCF₃ F307(a and b) NH—CH₃ —H -tert-butyl F308(a and b) NH —CH₃ —H -iso-propyl F309(a and b)NH —CF₃ —Cl —H F310(a and b) NH —CF₃ —Br —H F311(a and b) NH —CF₃ —F —HF312(a and b) NH —CF₃ —CH₃ —H F313(a and b) NH —CF₃ —CF₃ —H F314(a andb) NH —CF₃ —OCH₃ —H F315(a and b) NH —CF₃ —OCH₂CH₃ —H F316(a and b) NH—CF₃ —OCF₃ —H F317(a and b) NH —CF₃ -tert-butyl —H F318(a and b) NH —CF₃-iso-propyl —H F319(a and b) NH —CF₃ —CH₃ —CH₃ F320(a and b) NH —CF₃ —H—H F321(a and b) NH —CF₃ —H —Cl F322(a and b) NH —CF₃ —H —Br F323(a andb) NH —CF₃ —H —F F324(a and b) NH —CF₃ —H —CH₃ F325(a and b) NH —CF₃ —H—CF₃ F326(a and b) NH —CF₃ —H —OCH₃ F327(a and b) NH —CF₃ —H —OCH₂CH₃F328(a and b) NH —CF₃ —H —OCF₃ F329(a and b) NH —CF₃ —H -tert-butylF330(a and b) NH —CF₃ —H -iso-propyl F331(a and b) NH —CHF₂ —Cl —HF332(a and b) NH —CHF₂ —Br —H F333(a and b) NH —CHF₂ —F —H F334(a and b)NH —CHF₂ —CH₃ —H F335(a and b) NH —CHF₂ —CF₃ —H F336(a and b) NH —CHF₂—OCH₃ —H F337(a and b) NH —CHF₂ —OCH₂CH₃ —H F338(a and b) NH —CHF₂ —OCF₃—H F339(a and b) NH —CHF₂ -tert-butyl —H F340(a and b) NH —CHF₂-iso-propyl —H F341(a and b) NH —CHF₂ —CH₃ —CH₃ F342(a and b) NH —CHF₂—H —H F343(a and b) NH —CHF₂ —H —Cl F344(a and b) NH —CHF₂ —H —Br F345(aand b) NH —CHF₂ —H —F F346(a and b) NH —CHF₂ —H —CH₃ F347(a and b) NH—CHF₂ —H —CF₃ F348(a and b) NH —CHF₂ —H —OCH₃ F349(a and b) NH —CHF₂ —H—OCH₂CH₃ F350(a and b) NH —CHF₂ —H —OCF₃ F351(a and b) NH —CHF₂ —H-tert-butyl F352(a and b) NH —CHF₂ —H -iso-propyl F353(a and b) NH —Br—Br —H F354(a and b) NH —Br —Cl —H F355(a and b) NH —Br —F —H F356(a andb) NH —Br —CH₃ —H F357(a and b) NH —Br —CF₃ —H F358(a and b) NH —Br—OCH₃ —H F359(a and b) NH —Br —OCH₂CH₃ —H F360(a and b) NH —Br —OCF₃ —HF361(a and b) NH —Br -tert-butyl —H F362(a and b) NH —Br -iso-propyl —HF363(a and b) NH —Br —CH₃ —CH₃ F364(a and b) NH —Br —H —H F365(a and b)NH —Br —H —Cl F366(a and b) NH —Br —H —Br F367(a and b) NH —Br —H —FF368(a and b) NH —Br —H —CH₃ F369(a and b) NH —Br —H —CF₃ F370(a and b)NH —Br —H —OCH₃ F371(a and b) NH —Br —H —OCH₂CH₃ F372(a and b) NH —Br —H—OCF₃ F373(a and b) NH —Br —H -tert-butyl F374(a and b) NH —Br —H-iso-propyl F375(a and b) NH —I —Cl —H F376(a and b) NH —I —Br —H F377(aand b) NH —I —F —H F378(a and b) NH —I —CH₃ —H F379(a and b) NH —I —CF₃—H F380(a and b) NH —I —OCH₃ —H F381(a and b) NH —I —OCH₂CH₃ —H F382(aand b) NH —I —OCF₃ —H F383(a and b) NH —I -tert-butyl —H F384(a and b)NH —I -iso-propyl —H F385(a and b) NH —I —CH₃ —CH₃ F386(a and b) NH —I—H —H F387(a and b) NH —I —H —Cl F388(a and b) NH —I —H —Br F389(a andb) NH —I —H —F F390(a and b) NH —I —H —CH₃ F391(a and b) NH —I —H —CF₃F392(a and b) NH —I —H —OCH₃ F393(a and b) NH —I —H —OCH₂CH₃ F394(a andb) NH —I —H —OCF₃ F395(a and b) NH —I —H -tert-butyl F396(a and b) NH —I—H -iso-propyl In the column labeled “Compound”: (a) means Z₁ is CH andZ₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 7 (IX)

Compound Y R₁ (R₈)_(a) (R₈)_(b) G1(a and b) S —Cl —Cl —H G2(a and b) S—Cl —Br —H G3(a and b) S —Cl —F —H G4(a and b) S —Cl —CH₃ —H G5(a and b)S —Cl —CF₃ —H G6(a and b) S —Cl —OCH₃ —H G7(a and b) S —Cl —OCH₂CH₃ —HG8(a and b) S —Cl —OCF₃ —H G9(a and b) S —Cl -tert-butyl —H G10(a and b)S —Cl -iso-propyl —H G11(a and b) S —Cl —CH₃ —CH₃ G12(a and b) S —Cl —H—H G13(a and b) S —Cl —H —Cl G14(a and b) S —Cl —H —Br G15(a and b) S—Cl —H —F G16(a and b) S —Cl —H —CH₃ G17(a and b) S —Cl —H —CF₃ G18(aand b) S —Cl —H —OCH₃ G19(a and b) S —Cl —H —OCH₂CH₃ G20(a and b) S —Cl—H —OCF₃ G21(a and b) S —Cl —H -tert-butyl G22(a and b) S —Cl —H-iso-propyl G23(a and b) S —CH₃ —Cl —H G24(a and b) S —CH₃ —Br —H G25(aand b) S —CH₃ —F —H G26(a and b) S —CH₃ —CH₃ —H G27(a and b) S —CH₃ —CF₃—H G28(a and b) S —CH₃ —OCH₃ —H G29(a and b) S —CH₃ —OCH₂CH₃ —H G30(aand b) S —CH₃ —OCF₃ —H G31(a and b) S —CH₃ -tert-butyl —H G32(a and b) S—CH₃ -iso-propyl —H G33(a and b) S —CH₃ —CH₃ —CH₃ G34(a and b) S —CH₃ —H—H G35(a and b) S —CH₃ —H —Cl G36(a and b) S —CH₃ —H —Br G37(a and b) S—CH₃ —H —F G38(a and b) S —CH₃ —H —CH₃ G39(a and b) S —CH₃ —H —CF₃ G40(aand b) S —CH₃ —H —OCH₃ G41(a and b) S —CH₃ —H —OCH₂CH₃ G42(a and b) S—CH₃ —H —OCF₃ G43(a and b) S —CH₃ —H -tert-butyl G44(a and b) S —CH₃ —H-iso-propyl G45(a and b) S —CF₃ —Cl —H G46(a and b) S —CF₃ —Br —H G47(aand b) S —CF₃ —F —H G48(a and b) S —CF₃ —CH₃ —H G49(a and b) S —CF₃ —CF₃—H G50(a and b) S —CF₃ —OCH₃ —H G51(a and b) S —CF₃ —OCH₂CH₃ —H G52(aand b) S —CF₃ —OCF₃ —H G53(a and b) S —CF₃ -tert-butyl —H G54(a and b) S—CF₃ -iso-propyl —H G55(a and b) S —CF₃ —CH₃ —CH₃ G56(a and b) S —CF₃ —H—H G57(a and b) S —CF₃ —H —Cl G58(a and b) S —CF₃ —H —Br G59(a and b) S—CF₃ —H —F G60(a and b) S —CF₃ —H —CH₃ G61(a and b) S —CF₃ —H —CF₃ G62(aand b) S —CF₃ —H —OCH₃ G63(a and b) S —CF₃ —H —OCH₂CH₃ G64(a and b) S—CF₃ —H —OCF₃ G65(a and b) S —CF₃ —H -tert-butyl G66(a and b) S —CF₃ —H-iso-propyl G67(a and b) S —CHF₂ —Cl —H G68(a and b) S —CHF₂ —Br —HG69(a and b) S —CHF₂ —F —H G70(a and b) S —CHF₂ —CH₃ —H G71(a and b) S—CHF₂ —CF₃ —H G72(a and b) S —CHF₂ —OCH₃ —H G73(a and b) S —CHF₂—OCH₂CH₃ —H G74(a and b) S —CHF₂ —OCF₃ —H G75(a and b) S —CHF₂-tert-butyl —H G76(a and b) S —CHF₂ -iso-propyl —H G77(a and b) S —CHF₂—CH₃ —CH₃ G78(a and b) S —CHF₂ —H —H G79(a and b) S —CHF₂ —H —Cl G80(aand b) S —CHF₂ —H —Br G81(a and b) S —CHF₂ —H —F G82(a and b) S —CHF₂ —H—CH₃ G83(a and b) S —CHF₂ —H —CF₃ G84(a and b) S —CHF₂ —H —OCH₃ G85(aand b) S —CHF₂ —H —OCH₂CH₃ G86(a and b) S —CHF₂ —H —OCF₃ G87(a and b) S—CHF₂ —H -tert-butyl G88(a and b) S —CHF₂ —H -iso-propyl G89(a and b) S—Br —Br —H G90(a and b) S —Br —Cl —H G91(a and b) S —Br —F —H G92(a andb) S —Br —CH₃ —H G93(a and b) S —Br —CF₃ —H G94(a and b) S —Br —OCH₃ —HG95(a and b) S —Br —OCH₂CH₃ —H G96(a and b) S —Br —OCF₃ —H G97(a and b)S —Br -tert-butyl —H G98(a and b) S —Br -iso-propyl —H G99(a and b) S—Br —CH₃ —CH₃ G100(a and b) S —Br —H —H G101(a and b) S —Br —H —ClG102(a and b) S —Br —H —Br G103(a and b) S —Br —H —F G104(a and b) S —Br—H —CH₃ G105(a and b) S —Br —H —CF₃ G106(a and b) S —Br —H —OCH₃ G107(aand b) S —Br —H —OCH₂CH₃ G108(a and b) S —Br —H —OCF₃ G109(a and b) S—Br —H -tert-butyl G110(a and b) S —Br —H -iso-propyl G111(a and b) S —I—Cl —H G112(a and b) S —I —Br —H G113(a and b) S —I —F —H G114(a and b)S —I —CH₃ —H G115(a and b) S —I —CF₃ —H G116(a and b) S —I —OCH₃ —HG117(a and b) S —I —OCH₂CH₃ —H G118(a and b) S —I —OCF₃ —H G119(a and b)S —I -tert-butyl —H G120(a and b) S —I -iso-propyl —H G121(a and b) S —I—CH₃ —CH₃ G122(a and b) S —I —H —H G123(a and b) S —I —H —Cl G124(a andb) S —I —H —Br G125(a and b) S —I —H —F G126(a and b) S —I —H —CH₃G127(a and b) S —I —H —CF₃ G128(a and b) S —I —H —OCH₃ G129(a and b) S—I —H —OCH₂CH₃ G130(a and b) S —I —H —OCF₃ G131(a and b) S —I —H-tert-butyl G132(a and b) S —I —H -iso-propyl G133(a and b) O —Cl —Cl —HG134(a and b) O —Cl —Br —H G135(a and b) O —Cl —F —H G136(a and b) O —Cl—CH₃ —H G137(a and b) O —Cl —CF₃ —H G138(a and b) O —Cl —OCH₃ —H G139(aand b) O —Cl —OCH₂CH₃ —H G140(a and b) O —Cl —OCF₃ —H G141(a and b) O—Cl -tert-butyl —H G142(a and b) O —Cl -iso-propyl —H G143(a and b) O—Cl —CH₃ —CH₃ G144(a and b) O —Cl —H —H G145(a and b) O —Cl —H —CH₃G146(a and b) O —Cl —H —Cl G147(a and b) O —Cl —H —Br G148(a and b) O—Cl —H —F G149(a and b) O —Cl —H —CF₃ G150(a and b) O —Cl —H —OCH₃G151(a and b) O —Cl —H —OCH₂CH₃ G152(a and b) O —Cl —H —OCF₃ G153(a andb) O —Cl —H -tert-butyl G154(a and b) O —Cl —H -iso-propyl G155(a and b)O —CH₃ —Cl —H G156(a and b) O —CH₃ —Br —H G157(a and b) O —CH₃ —F —HG158(a and b) O —CH₃ —CH₃ —H G159(a and b) O —CH₃ —CF₃ —H G160(a and b)O —CH₃ —OCH₃ —H G161(a and b) O —CH₃ —OCH₂CH₃ —H G162(a and b) O —CH₃—OCF₃ —H G163(a and b) O —CH₃ -tert-butyl —H G164(a and b) O —CH₃-iso-propyl —H G165(a and b) O —CH₃ —CH₃ —CH₃ G166(a and b) O —CH₃ —H —HG167(a and b) O —CH₃ —H —Cl G168(a and b) O —CH₃ —H —Br G169(a and b) O—CH₃ —H —F G170(a and b) O —CH₃ —H —CH₃ G171(a and b) O —CH₃ —H —CF₃G172(a and b) O —CH₃ —H —OCH₃ G173(a and b) O —CH₃ —H —OCH₂CH₃ G174(aand b) O —CH₃ —H —OCF₃ G175(a and b) O —CH₃ —H -tert-butyl G176(a and b)O —CH₃ —H -iso-propyl G177(a and b) O —CF₃ —Cl —H G178(a and b) O —CF₃—Br —H G179(a and b) O —CF₃ —F —H G180(a and b) O —CF₃ —CH₃ —H G181(aand b) O —CF₃ —CF₃ —H G182(a and b) O —CF₃ —OCH₃ —H G183(a and b) O —CF₃—OCH₂CH₃ —H G184(a and b) O —CF₃ —OCF₃ —H G185(a and b) O —CF₃-tert-butyl —H G186(a and b) O —CF₃ -iso-propyl —H G187(a and b) O —CF₃—CH₃ —CH₃ G188(a and b) O —CF₃ —H —H G189(a and b) O —CF₃ —H —Cl G190(aand b) O —CF₃ —H —Br G191(a and b) O —CF₃ —H —F G192(a and b) O —CF₃ —H—CH₃ G193(a and b) O —CF₃ —H —CF₃ G194(a and b) O —CF₃ —H —OCH₃ G195(aand b) O —CF₃ —H —OCH₂CH₃ G196(a and b) O —CF₃ —H —OCF₃ G197(a and b) O—CF₃ —H -tert-butyl G198(a and b) O —CF₃ —H -iso-propyl G199(a and b) O—CHF₂ —Cl —H G200(a and b) O —CHF₂ —Br —H G201(a and b) O —CHF₂ —F —HG202(a and b) O —CHF₂ —CH₃ —H G203(a and b) O —CHF₂ —CF₃ —H G204(a andb) O —CHF₂ —OCH₃ —H G205(a and b) O —CHF₂ —OCH₂CH₃ —H G206(a and b) O—CHF₂ —OCF₃ —H G207(a and b) O —CHF₂ -tert-butyl —H G208(a and b) O—CHF₂ -iso-propyl —H G209(a and b) O —CHF₂ —CH₃ —CH₃ G210(a and b) O—CHF₂ —H —H G211(a and b) O —CHF₂ —H —Cl G212(a and b) O —CHF₂ —H —BrG213(a and b) O —CHF₂ —H —F G214(a and b) O —CHF₂ —H —CH₃ G215(a and b)O —CHF₂ —H —CF₃ G216(a and b) O —CHF₂ —H —OCH₃ G217(a and b) O —CHF₂ —H—OCH₂CH₃ G218(a and b) O —CHF₂ —H —OCF₃ G219(a and b) O —CHF₂ —H-tert-butyl G220(a and b) O —CHF₂ —H -iso-propyl G221(a and b) O —Br —Br—H G222(a and b) O —Br —Cl —H G223(a and b) O —Br —F —H G224(a and b) O—Br —CH₃ —H G225(a and b) O —Br —CF₃ —H G226(a and b) O —Br —OCH₃ —HG227(a and b) O —Br —OCH₂CH₃ —H G228(a and b) O —Br —OCF₃ —H G229(a andb) O —Br -tert-butyl —H G230(a and b) O —Br -iso-propyl —H G231(a and b)O —Br —CH₃ —CH₃ G232(a and b) O —Br —H —H G233(a and b) O —Br —H —ClG234(a and b) O —Br —H —Br G235(a and b) O —Br —H —F G236(a and b) O —Br—H —CH₃ G237(a and b) O —Br —H —CF₃ G238(a and b) O —Br —H —OCH₃ G239(aand b) O —Br —H —OCH₂CH₃ G240(a and b) O —Br —H —OCF₃ G241(a and b) O—Br —H -tert-butyl G242(a and b) O —Br —H -iso-propyl G243(a and b) O —I—Cl —H G244(a and b) O —I —Br —H G245(a and b) O —I —F —H G246(a and b)O —I —CH₃ —H G247(a and b) O —I —CF₃ —H G248(a and b) O —I —OCH₃ —HG249(a and b) O —I —OCH₂CH₃ —H G250(a and b) O —I —OCF₃ —H G251(a and b)O —I -tert-butyl —H G252(a and b) O —I -iso-propyl —H G253(a and b) O —I—CH₃ —CH₃ G254(a and b) O —I —H —H G255(a and b) O —I —H —Cl G256(a andb) O —I —H —Br G257(a and b) O —I —H —F G258(a and b) O —I —H —CH₃G259(a and b) O —I —H —CF₃ G260(a and b) O —I —H —OCH₃ G261(a and b) O—I —H —OCH₂CH₃ G262(a and b) O —I —H —OCF₃ G263(a and b) O —I —H-tert-butyl G264(a and b) O —I —H -iso-propyl G265(a and b) NH —Cl —Cl—H G266(a and b) NH —Cl —Br —H G267(a and b) NH —Cl —F —H G268(a and b)NH —Cl —CH₃ —H G269(a and b) NH —Cl —CF₃ —H G270(a and b) NH —Cl —OCH₃—H G271(a and b) NH —Cl —OCH₂CH₃ —H G272(a and b) NH —Cl —OCF₃ —H G273(aand b) NH —Cl -tert-butyl —H G274(a and b) NH —Cl -iso-propyl —H G275(aand b) NH —Cl —CH₃ —CH₃ G276(a and b) NH —Cl —H —H G277(a and b) NH —Cl—H —CH₃ G278(a and b) NH —Cl —H —Cl G279(a and b) NH —Cl —H —Br G280(aand b) NH —Cl —H —F G281(a and b) NH —Cl —H —CF₃ G282(a and b) NH —Cl —H—OCH₃ G283(a and b) NH —Cl —H —OCH₂CH₃ G284(a and b) NH —Cl —H —OCF₃G285(a and b) NH —Cl —H -tert-butyl G286(a and b) NH —Cl —H -iso-propylG287(a and b) NH —CH₃ —Cl —H G288(a and b) NH —CH₃ —Br —H G289(a and b)NH —CH₃ —F —H G290(a and b) NH —CH₃ —CH₃ —H G291(a and b) NH —CH₃ —CF₃—H G292(a and b) NH —CH₃ —OCH₃ —H G293(a and b) NH —CH₃ —OCH₂CH₃ —HG294(a and b) NH —CH₃ —OCF₃ —H G295(a and b) NH —CH₃ -tert-butyl —HG296(a and b) NH —CH₃ -iso-propyl —H G297(a and b) NH —CH₃ —CH₃ —CH₃G298(a and b) NH —CH₃ —H —H G299(a and b) NH —CH₃ —H —Cl G300(a and b)NH —CH₃ —H —Br G301(a and b) NH —CH₃ —H —F G302(a and b) NH —CH₃ —H —CH₃G303(a and b) NH —CH₃ —H —CF₃ G304(a and b) NH —CH₃ —H —OCH₃ G305(a andb) NH —CH₃ —H —OCH₂CH₃ G306(a and b) NH —CH₃ —H —OCF₃ G307(a and b) NH—CH₃ —H -tert-butyl G308(a and b) NH —CH₃ —H -iso-propyl G309(a and b)NH —CF₃ —Cl —H G310(a and b) NH —CF₃ —Br —H G311(a and b) NH —CF₃ —F —HG312(a and b) NH —CF₃ —CH₃ —H G313(a and b) NH —CF₃ —CF₃ —H G314(a andb) NH —CF₃ —OCH₃ —H G315(a and b) NH —CF₃ —OCH₂CH₃ —H G316(a and b) NH—CF₃ —OCF₃ —H G317(a and b) NH —CF₃ -tert-butyl —H G318(a and b) NH —CF₃-iso-propyl —H G319(a and b) NH —CF₃ —CH₃ —CH₃ G320(a and b) NH —CF₃ —H—H G321(a and b) NH —CF₃ —H —Cl G322(a and b) NH —CF₃ —H —Br G323(a andb) NH —CF₃ —H —F G324(a and b) NH —CF₃ —H —CH₃ G325(a and b) NH —CF₃ —H—CF₃ G326(a and b) NH —CF₃ —H —OCH₃ G327(a and b) NH —CF₃ —H —OCH₂CH₃G328(a and b) NH —CF₃ —H —OCF₃ G329(a and b) NH —CF₃ —H -tert-butylG330(a and b) NH —CF₃ —H -iso-propyl G331(a and b) NH —CHF₂ —Cl —HG332(a and b) NH —CHF₂ —Br —H G333(a and b) NH —CHF₂ —F —H G334(a and b)NH —CHF₂ —CH₃ —H G335(a and b) NH —CHF₂ —CF₃ —H G336(a and b) NH —CHF₂—OCH₃ —H G337(a and b) NH —CHF₂ —OCH₂CH₃ —H G338(a and b) NH —CHF₂ —OCF₃—H G339(a and b) NH —CHF₂ -tert-butyl —H G340(a and b) NH —CHF₂-iso-propyl —H G341(a and b) NH —CHF₂ —CH₃ —CH₃ G342(a and b) NH —CHF₂—H —H G343(a and b) NH —CHF₂ —H —Cl G344(a and b) NH —CHF₂ —H —Br G345(aand b) NH —CHF₂ —H —F G346(a and b) NH —CHF₂ —H —CH₃ G347(a and b) NH—CHF₂ —H —CF₃ G348(a and b) NH —CHF₂ —H —OCH₃ G349(a and b) NH —CHF₂ —H—OCH₂CH₃ G350(a and b) NH —CHF₂ —H —OCF₃ G351(a and b) NH —CHF₂ —H-tert-butyl G352(a and b) NH —CHF₂ —H -iso-propyl G353(a and b) NH —Br—Br —H G354(a and b) NH —Br —Cl —H G355(a and b) NH —Br —F —H G356(a andb) NH —Br —CH₃ —H G357(a and b) NH —Br —CF₃ —H G358(a and b) NH —Br—OCH₃ —H G359(a and b) NH —Br —OCH₂CH₃ —H G360(a and b) NH —Br —OCF₃ —HG361(a and b) NH —Br -tert-butyl —H G362(a and b) NH —Br -iso-propyl —HG363(a and b) NH —Br —CH₃ —CH₃ G364(a and b) NH —Br —H —H G365(a and b)NH —Br —H —Cl G366(a and b) NH —Br —H —Br G367(a and b) NH —Br —H —FG368(a and b) NH —Br —H —CH₃ G369(a and b) NH —Br —H —CF₃ G370(a and b)NH —Br —H —OCH₃ G371(a and b) NH —Br —H —OCH₂CH₃ G372(a and b) NH —Br —H—OCF₃ G373(a and b) NH —Br —H -tert-butyl G374(a and b) NH —Br —H-iso-propyl G375(a and b) NH —I —Cl —H G376(a and b) NH —I —Br —H G377(aand b) NH —I —F —H G378(a and b) NH —I —CH₃ —H G379(a and b) NH —I —CF₃—H G380(a and b) NH —I —OCH₃ —H G381(a and b) NH —I —OCH₂CH₃ —H G382(aand b) NH —I —OCF₃ —H G383(a and b) NH —I -tert-butyl —H G384(a and b)NH —I -iso-propyl —H G385(a and b) NH —I —CH₃ —CH₃ G386(a and b) NH —I—H —H G387(a and b) NH —I —H —Cl G388(a and b) NH —I —H —Br G389(a andb) NH —I —H —F G390(a and b) NH —I —H —CH₃ G391(a and b) NH —I —H —CF₃G392(a and b) NH —I —H —OCH₃ G393(a and b) NH —I —H —OCH₂CH₃ G394(a andb) NH —I —H —OCF₃ G395(a and b) NH —I —H -tert-butyl G396(a and b) NH —I—H -iso-propyl In the column labeled “Compound”: (a) means Z₁ is CH andZ₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 8 (X)

Compound Y R₁ (R₈)_(a) (R₈)_(b) H1 (a) and (b) S —Cl —Cl —H H2 (a) and(b) S —Cl —Br —H H3 (a) and (b) S —Cl —F —H H4 (a) and (b) S —Cl —CH₃ —HH5 (a) and (b) S —Cl —CF₃ —H H6 (a) and (b) S —Cl —OCH₃ —H H7 (a) and(b) S —Cl —OCH₂CH₃ —H H8 (a) and (b) S —Cl —OCF₃ —H H9 (a) and (b) S —Cl-tert-butyl —H H10 (a) and (b) S —Cl -iso-propyl —H H11 (a) and (b) S—Cl —CH₃ —CH₃ H12 (a) and (b) S —Cl —H —H H13 (a) and (b) S —Cl —H —ClH14 (a) and (b) S —Cl —H —Br H15 (a) and (b) S —Cl —H —F H16 (a) and (b)S —Cl —H —CH₃ H17 (a) and (b) S —Cl —H —CF₃ H18 (a) and (b) S —Cl —H—OCH₃ H19 (a) and (b) S —Cl —H —OCH₂CH₃ H20 (a) and (b) S —Cl —H —OCF₃H21 (a) and (b) S —Cl —H -tert-butyl H22 (a) and (b) S —Cl —H-iso-propyl H23 (a) and (b) S —CH₃ —Cl —H H24 (a) and (b) S —CH₃ —Br —HH25 (a) and (b) S —CH₃ —F —H H26 (a) and (b) S —CH₃ —CH₃ —H H27 (a) and(b) S —CH₃ —CF₃ —H H28 (a) and (b) S —CH₃ —OCH₃ —H H29 (a) and (b) S—CH₃ —OCH₂CH₃ —H H30 (a) and (b) S —CH₃ —OCF₃ —H H31 (a) and (b) S —CH₃-tert-butyl —H H32 (a) and (b) S —CH₃ -iso-propyl —H H33 (a) and (b) S—CH₃ —CH₃ —CH₃ H34 (a) and (b) S —CH₃ —H —H H35 (a) and (b) S —CH₃ —H—Cl H36 (a) and (b) S —CH₃ —H —Br H37 (a) and (b) S —CH₃ —H —F H38 (a)and (b) S —CH₃ —H —CH₃ H39 (a) and (b) S —CH₃ —H —CF₃ H40 (a) and (b) S—CH₃ —H —OCH₃ H41 (a) and (b) S —CH₃ —H —OCH₂CH₃ H42 (a) and (b) S —CH₃—H —OCF₃ H43 (a) and (b) S —CH₃ —H -tert-butyl H44 (a) and (b) S —CH₃ —H-iso-propyl H45 (a) and (b) S —CF₃ —Cl —H H46 (a) and (b) S —CF₃ —Br —HH47 (a) and (b) S —CF₃ —F —H H48 (a) and (b) S —CF₃ —CH₃ —H H49 (a) and(b) S —CF₃ —CF₃ —H H50 (a) and (b) S —CF₃ —OCH₃ —H H51 (a) and (b) S—CF₃ —OCH₂CH₃ —H H52 (a) and (b) S —CF₃ —OCF₃ —H H53 (a) and (b) S —CF₃-tert-butyl —H H54 (a) and (b) S —CF₃ -iso-propyl —H H55 (a) and (b) S—CF₃ —CH₃ —CH₃ H56 (a) and (b) S —CF₃ —H —H H57 (a) and (b) S —CF₃ —H—Cl H58 (a) and (b) S —CF₃ —H —Br H59 (a) and (b) S —CF₃ —H —F H60 (a)and (b) S —CF₃ —H —CH₃ H61 (a) and (b) S —CF₃ —H —CF₃ H62 (a) and (b) S—CF₃ —H —OCH₃ H63 (a) and (b) S —CF₃ —H —OCH₂CH₃ H64 (a) and (b) S —CF₃—H —OCF₃ H65 (a) and (b) S —CF₃ —H -tert-butyl H66 (a) and (b) S —CF₃ —H-iso-propyl H67 (a) and (b) S —CHF₂ —Cl —H H68 (a) and (b) S —CHF₂ —Br—H H69 (a) and (b) S —CHF₂ —F —H H70 (a) and (b) S —CHF₂ —CH₃ —H H71 (a)and (b) S —CHF₂ —CF₃ —H H72 (a) and (b) S —CHF₂ —OCH₃ —H H73 (a) and (b)S —CHF₂ —OCH₂CH₃ —H H74 (a) and (b) S —CHF₂ —OCF₃ —H H75 (a) and (b) S—CHF₂ -tert-butyl —H H76 (a) and (b) S —CHF₂ -iso-propyl —H H77 (a) and(b) S —CHF₂ —CH₃ —CH₃ H78 (a) and (b) S —CHF₂ —H —H H79 (a) and (b) S—CHF₂ —H —Cl H80 (a) and (b) S —CHF₂ —H —Br H81 (a) and (b) S —CHF₂ —H—F H82 (a) and (b) S —CHF₂ —H —CH₃ H83 (a) and (b) S —CHF₂ —H —CF₃ H84(a) and (b) S —CHF₂ —H —OCH₃ H85 (a) and (b) S —CHF₂ —H —OCH₂CH₃ H86 (a)and (b) S —CHF₂ —H —OCF₃ H87 (a) and (b) S —CHF₂ —H -tert-butyl H88 (a)and (b) S —CHF₂ —H -iso-propyl H89 (a) and (b) S —Br —Br —H H90 (a) and(b) S —Br —Cl —H H91 (a) and (b) S —Br —F —H H92 (a) and (b) S —Br —CH₃—H H93 (a) and (b) S —Br —CF₃ —H H94 (a) and (b) S —Br —OCH₃ —H H95 (a)and (b) S —Br —OCH₂CH₃ —H H96 (a) and (b) S —Br —OCF₃ —H H97 (a) and (b)S —Br -tert-butyl —H H98 (a) and (b) S —Br -iso-propyl —H H99 (a) and(b) S —Br —CH₃ —CH₃ H100 (a) and (b) S —Br —H —H H101 (a) and (b) S —Br—H —Cl H102 (a) and (b) S —Br —H —Br H103 (a) and (b) S —Br —H —F H104(a) and (b) S —Br —H —CH₃ H105 (a) and (b) S —Br —H —CF₃ H106 (a) and(b) S —Br —H —OCH₃ H107 (a) and (b) S —Br —H —OCH₂CH₃ H108 (a) and (b) S—Br —H —OCF₃ H109 (a) and (b) S —Br —H -tert-butyl H110 (a) and (b) S—Br —H -iso-propyl H111 (a) and (b) S —I —Cl —H H112 (a) and (b) S —I—Br —H H113 (a) and (b) S —I —F —H H114 (a) and (b) S —I —CH₃ —H H115(a) and (b) S —I —CF₃ —H H116 (a) and (b) S —I —OCH₃ —H H117 (a) and (b)S —I —OCH₂CH₃ —H H118 (a) and (b) S —I —OCF₃ —H H119 (a) and (b) S —I-tert-butyl —H H120 (a) and (b) S —I -iso-propyl —H H121 (a) and (b) S—I —CH₃ —CH₃ H122 (a) and (b) S —I —H —H H123 (a) and (b) S —I —H —ClH124 (a) and (b) S —I —H —Br H125 (a) and (b) S —I —H —F H126 (a) and(b) S —I —H —CH₃ H127 (a) and (b) S —I —H —CF₃ H128 (a) and (b) S —I —H—OCH₃ H129 (a) and (b) S —I —H —OCH₂CH₃ H130 (a) and (b) S —I —H —OCF₃H131 (a) and (b) S —I —H -tert-butyl H132 (a) and (b) S —I —H-iso-propyl H133 (a) and (b) O —Cl —Cl —H H134 (a) and (b) O —Cl —Br —HH135 (a) and (b) O —Cl —F —H H136 (a) and (b) O —Cl —CH₃ —H H137 (a) and(b) O —Cl —CF₃ —H H138 (a) and (b) O —Cl —OCH₃ —H H139 (a) and (b) O —Cl—OCH₂CH₃ —H H140 (a) and (b) O —Cl —OCF₃ —H H141 (a) and (b) O —Cl-tert-butyl —H H142 (a) and (b) O —Cl -iso-propyl —H H143 (a) and (b) O—Cl —CH₃ —CH₃ H144 (a) and (b) O —Cl —H —H H145 (a) and (b) O —Cl —H—CH₃ H146 (a) and (b) O —Cl —H —Cl H147 (a) and (b) O —Cl —H —Br H148(a) and (b) O —Cl —H —F H149 (a) and (b) O —Cl —H —CF₃ H150 (a) and (b)O —Cl —H —OCH₃ H151 (a) and (b) O —Cl —H —OCH₂CH₃ H152 (a) and (b) O —Cl—H —OCF₃ H153 (a) and (b) O —Cl —H -tert-butyl H154 (a) and (b) O —Cl —H-iso-propyl H155 (a) and (b) O —CH₃ —Cl —H H156 (a) and (b) O —CH₃ —Br—H H157 (a) and (b) O —CH₃ —F —H H158 (a) and (b) O —CH₃ —CH₃ —H H159(a) and (b) O —CH₃ —CF₃ —H H160 (a) and (b) O —CH₃ —OCH₃ —H H161 (a) and(b) O —CH₃ —OCH₂CH₃ —H H162 (a) and (b) O —CH₃ —OCF₃ —H H163 (a) and (b)O —CH₃ -tert-butyl —H H164 (a) and (b) O —CH₃ -iso-propyl —H H165 (a)and (b) O —CH₃ —CH₃ —CH₃ H166 (a) and (b) O —CH₃ —H —H H167 (a) and (b)O —CH₃ —H —Cl H168 (a) and (b) O —CH₃ —H —Br H169 (a) and (b) O —CH₃ —H—F H170 (a) and (b) O —CH₃ —H —CH₃ H171 (a) and (b) O —CH₃ —H —CF₃ H172(a) and (b) O —CH₃ —H —OCH₃ H173 (a) and (b) O —CH₃ —H —OCH₂CH₃ H174 (a)and (b) O —CH₃ —H —OCF₃ H175 (a) and (b) O —CH₃ —H -tert-butyl H176 (a)and (b) O —CH₃ —H -iso-propyl H177 (a) and (b) O —CF₃ —Cl —H H178 (a)and (b) O —CF₃ —Br —H H179 (a) and (b) O —CF₃ —F —H H180 (a) and (b) O—CF₃ —CH₃ —H H181 (a) and (b) O —CF₃ —CF₃ —H H182 (a) and (b) O —CF₃—OCH₃ —H H183 (a) and (b) O —CF₃ —OCH₂CH₃ —H H184 (a) and (b) O —CF₃—OCF₃ —H H185 (a) and (b) O —CF₃ -tert-butyl —H H186 (a) and (b) O —CF₃-iso-propyl —H H187 (a) and (b) O —CF₃ —CH₃ —CH₃ H188 (a) and (b) O —CF₃—H —H H189 (a) and (b) O —CF₃ —H —Cl H190 (a) and (b) O —CF₃ —H —Br H191(a) and (b) O —CF₃ —H —F H192 (a) and (b) O —CF₃ —H —CH₃ H193 (a) and(b) O —CF₃ —H —CF₃ H194 (a) and (b) O —CF₃ —H —OCH₃ H195 (a) and (b) O—CF₃ —H —OCH₂CH₃ H196 (a) and (b) O —CF₃ —H —OCF₃ H197 (a) and (b) O—CF₃ —H -tert-butyl H198 (a) and (b) O —CF₃ —H -iso-propyl H199 (a) and(b) O —CHF₂ —Cl —H H200 (a) and (b) O —CHF₂ —Br —H H201 (a) and (b) O—CHF₂ —F —H H202 (a) and (b) O —CHF₂ —CH₃ —H H203 (a) and (b) O —CHF₂—CF₃ —H H204 (a) and (b) O —CHF₂ —OCH₃ —H H205 (a) and (b) O —CHF₂—OCH₂CH₃ —H H206 (a) and (b) O —CHF₂ —OCF₃ —H H207 (a) and (b) O —CHF₂-tert-butyl —H H208 (a) and (b) O —CHF₂ -iso-propyl —H H209 (a) and (b)O —CHF₂ —CH₃ —CH₃ H210 (a) and (b) O —CHF₂ —H —H H211 (a) and (b) O—CHF₂ —H —Cl H212 (a) and (b) O —CHF₂ —H —Br H213 (a) and (b) O —CHF₂ —H—F H214 (a) and (b) O —CHF₂ —H —CH₃ H215 (a) and (b) O —CHF₂ —H —CF₃H216 (a) and (b) O —CHF₂ —H —OCH₃ H217 (a) and (b) O —CHF₂ —H —OCH₂CH₃H218 (a) and (b) O —CHF₂ —H —OCF₃ H219 (a) and (b) O —CHF₂ —H-tert-butyl H220 (a) and (b) O —CHF₂ —H -iso-propyl H221 (a) and (b) O—Br —Br —H H222 (a) and (b) O —Br —Cl —H H223 (a) and (b) O —Br —F —HH224 (a) and (b) O —Br —CH₃ —H H225 (a) and (b) O —Br —CF₃ —H H226 (a)and (b) O —Br —OCH₃ —H H227 (a) and (b) O —Br —OCH₂CH₃ —H H228 (a) and(b) O —Br —OCF₃ —H H229 (a) and (b) O —Br -tert-butyl —H H230 (a) and(b) O —Br -iso-propyl —H H231 (a) and (b) O —Br —CH₃ —CH₃ H232 (a) and(b) O —Br —H —H H233 (a) and (b) O —Br —H —Cl H234 (a) and (b) O —Br —H—Br H235 (a) and (b) O —Br —H —F H236 (a) and (b) O —Br —H —CH₃ H237 (a)and (b) O —Br —H —CF₃ H238 (a) and (b) O —Br —H —OCH₃ H239 (a) and (b) O—Br —H —OCH₂CH₃ H240 (a) and (b) O —Br —H —OCF₃ H241 (a) and (b) O —Br—H -tert-butyl H242 (a) and (b) O —Br —H -iso-propyl H243 (a) and (b) O—I —Cl —H H244 (a) and (b) O —I —Br —H H245 (a) and (b) O —I —F —H H246(a) and (b) O —I —CH₃ —H H247 (a) and (b) O —I —CF₃ —H H248 (a) and (b)O —I —OCH₃ —H H249 (a) and (b) O —I —OCH₂CH₃ —H H250 (a) and (b) O —I—OCF₃ —H H251 (a) and (b) O —I -tert-butyl —H H252 (a) and (b) O —I-iso-propyl —H H253 (a) and (b) O —I —CH₃ —CH₃ H254 (a) and (b) O —I —H—H H255 (a) and (b) O —I —H —Cl H256 (a) and (b) O —I —H —Br H257 (a)and (b) O —I —H —F H258 (a) and (b) O —I —H —CH₃ H259 (a) and (b) O —I—H —CF₃ H260 (a) and (b) O —I —H —OCH₃ H261 (a) and (b) O —I —H —OCH₂CH₃H262 (a) and (b) O —I —H —OCF₃ H263 (a) and (b) O —I —H -tert-butyl H264(a) and (b) O —I —H -iso-propyl H265 (a) and (b) NH —Cl —Cl —H H266 (a)and (b) NH —Cl —Br —H H267 (a) and (b) NH —Cl —F —H H268 (a) and (b) NH—Cl —CH₃ —H H269 (a) and (b) NH —Cl —CF₃ —H H270 (a) and (b) NH —Cl—OCH₃ —H H271 (a) and (b) NH —Cl —OCH₂CH₃ —H H272 (a) and (b) NH —Cl—OCF₃ —H H273 (a) and (b) NH —Cl -tert-butyl —H H274 (a) and (b) NH —Cl-iso-propyl —H H275 (a) and (b) NH —Cl —CH₃ —CH₃ H276 (a) and (b) NH —Cl—H —H H277 (a) and (b) NH —Cl —H —CH₃ H278 (a) and (b) NH —Cl —H —ClH279 (a) and (b) NH —Cl —H —Br H280 (a) and (b) NH —Cl —H —F H281 (a)and (b) NH —Cl —H —CF₃ H282 (a) and (b) NH —Cl —H —OCH₃ H283 (a) and (b)NH —Cl —H —OCH₂CH₃ H284 (a) and (b) NH —Cl —H —OCF₃ H285 (a) and (b) NH—Cl —H -tert-butyl H286 (a) and (b) NH —Cl —H -iso-propyl H287 (a) and(b) NH —CH₃ —Cl —H H288 (a) and (b) NH —CH₃ —Br —H H289 (a) and (b) NH—CH₃ —F —H H290 (a) and (b) NH —CH₃ —CH₃ —H H291 (a) and (b) NH —CH₃—CF₃ —H H292 (a) and (b) NH —CH₃ —OCH₃ —H H293 (a) and (b) NH —CH₃—OCH₂CH₃ —H H294 (a) and (b) NH —CH₃ —OCF₃ —H H295 (a) and (b) NH —CH₃-tert-butyl —H H296 (a) and (b) NH —CH₃ -iso-propyl —H H297 (a) and (b)NH —CH₃ —CH₃ —CH₃ H298 (a) and (b) NH —CH₃ —H —H H299 (a) and (b) NH—CH₃ —H —Cl H300 (a) and (b) NH —CH₃ —H —Br H301 (a) and (b) NH —CH₃ —H—F H302 (a) and (b) NH —CH₃ —H —CH₃ H303 (a) and (b) NH —CH₃ —H —CF₃H304 (a) and (b) NH —CH₃ —H —OCH₃ H305 (a) and (b) NH —CH₃ —H —OCH₂CH₃H306 (a) and (b) NH —CH₃ —H —OCF₃ H307 (a) and (b) NH —CH₃ —H-tert-butyl H308 (a) and (b) NH —CH₃ —H -iso-propyl H309 (a) and (b) NH—CF₃ —Cl —H H310 (a) and (b) NH —CF₃ —Br —H H311 (a) and (b) NH —CF₃ —F—H H312 (a) and (b) NH —CF₃ —CH₃ —H H313 (a) and (b) NH —CF₃ —CF₃ —HH314 (a) and (b) NH —CF₃ —OCH₃ —H H315 (a) and (b) NH —CF₃ —OCH₂CH₃ —HH316 (a) and (b) NH —CF₃ —OCF₃ —H H317 (a) and (b) NH —CF₃ -tert-butyl—H H318 (a) and (b) NH —CF₃ -iso-propyl —H H319 (a) and (b) NH —CF₃ —CH₃—CH₃ H320 (a) and (b) NH —CF₃ —H —H H321 (a) and (b) NH —CF₃ —H —Cl H322(a) and (b) NH —CF₃ —H —Br H323 (a) and (b) NH —CF₃ —H —F H324 (a) and(b) NH —CF₃ —H —CH₃ H325 (a) and (b) NH —CF₃ —H —CF₃ H326 (a) and (b) NH—CF₃ —H —OCH₃ H327 (a) and (b) NH —CF₃ —H —OCH₂CH₃ H328 (a) and (b) NH—CF₃ —H —OCF₃ H329 (a) and (b) NH —CF₃ —H -tert-butyl H330 (a) and (b)NH —CF₃ —H -iso-propyl H331 (a) and (b) NH —CHF₂ —Cl —H H332 (a) and (b)NH —CHF₂ —Br —H H333 (a) and (b) NH —CHF₂ —F —H H334 (a) and (b) NH—CHF₂ —CH₃ —H H335 (a) and (b) NH —CHF₂ —CF₃ —H H336 (a) and (b) NH—CHF₂ —OCH₃ —H H337 (a) and (b) NH —CHF₂ —OCH₂CH₃ —H H338 (a) and (b) NH—CHF₂ —OCF₃ —H H339 (a) and (b) NH —CHF₂ -tert-butyl —H H340 (a) and (b)NH —CHF₂ -iso-propyl —H H341 (a) and (b) NH —CHF₂ —CH₃ —CH₃ H342 (a) and(b) NH —CHF₂ —H —H H343 (a) and (b) NH —CHF₂ —H —Cl H344 (a) and (b) NH—CHF₂ —H —Br H345 (a) and (b) NH —CHF₂ —H —F H346 (a) and (b) NH —CHF₂—H —CH₃ H347 (a) and (b) NH —CHF₂ —H —CF₃ H348 (a) and (b) NH —CHF₂ —H—OCH₃ H349 (a) and (b) NH —CHF₂ —H —OCH₂CH₃ H350 (a) and (b) NH —CHF₂ —H—OCF₃ H351 (a) and (b) NH —CHF₂ —H -tert-butyl H352 (a) and (b) NH —CHF₂—H -iso-propyl H353 (a) and (b) NH —Br —Br —H H354 (a) and (b) NH —Br—Cl —H H355 (a) and (b) NH —Br —F —H H356 (a) and (b) NH —Br —CH₃ —HH357 (a) and (b) NH —Br —CF₃ —H H358 (a) and (b) NH —Br —OCH₃ —H H359(a) and (b) NH —Br —OCH₂CH₃ —H H360 (a) and (b) NH —Br —OCF₃ —H H361 (a)and (b) NH —Br -tert-butyl —H H362 (a) and (b) NH —Br -iso-propyl —HH363 (a) and (b) NH —Br —CH₃ —CH₃ H364 (a) and (b) NH —Br —H —H H365 (a)and (b) NH —Br —H —Cl H366 (a) and (b) NH —Br —H —Br H367 (a) and (b) NH—Br —H —F H368 (a) and (b) NH —Br —H —CH₃ H369 (a) and (b) NH —Br —H—CF₃ H370 (a) and (b) NH —Br —H —OCH₃ H371 (a) and (b) NH —Br —H—OCH₂CH₃ H372 (a) and (b) NH —Br —H —OCF₃ H373 (a) and (b) NH —Br —H-tert-butyl H374 (a) and (b) NH —Br —H -iso-propyl H375 (a) and (b) NH—I —Cl —H H376 (a) and (b) NH —I —Br —H H377 (a) and (b) NH —I —F —HH378 (a) and (b) NH —I —CH₃ —H H379 (a) and (b) NH —I —CF₃ —H H380 (a)and (b) NH —I —OCH₃ —H H381 (a) and (b) NH —I —OCH₂CH₃ —H H382 (a) and(b) NH —I —OCF₃ —H H383 (a) and (b) NH —I -tert-butyl —H H384 (a) and(b) NH —I -iso-propyl —H H385 (a) and (b) NH —I —CH₃ —CH₃ H386 (a) and(b) NH —I —H —H H387 (a) and (b) NH —I —H —Cl H388 (a) and (b) NH —I —H—Br H389 (a) and (b) NH —I —H —F H390 (a) and (b) NH —I —H —CH₃ H391 (a)and (b) NH —I —H —CF₃ H392 (a) and (b) NH —I —H —OCH₃ H393 (a) and (b)NH —I —H —OCH₂CH₃ H394 (a) and (b) NH —I —H —OCF₃ H395 (a) and (b) NH —I—H -tert-butyl H396 (a) and (b) NH —I —H -iso-propyl In the columnlabeled “Compound”: (a) means Z₁ is CH and Z₂ is N; and (b) means Z₁ isN and Z₂ is CH.

TABLE 9 (XI)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) I1(a and b) S —Cl —Cl —H I2(a and b) S —Cl —Br —H I3(aand b) S —Cl —F —H I4(a and b) S —Cl —CH₃ —H I5(a and b) S —Cl —CF₃ —HI6(a and b) S —Cl —OCH₃ —H I7(a and b) S —Cl —OCH₂CH₃ —H I8(a and b) S—Cl —OCF₃ —H I9(a and b) S —Cl -tert-butyl —H I10(a and b) S —Cl-iso-propyl —H I11(a and b) S —Cl —CH₃ —CH₃ I12(a and b) S —Cl —H —HI13(a and b) S —Cl —H —Cl I14(a and b) S —Cl —H —Br I15(a and b) S —Cl—H —F I16(a and b) S —Cl —H —CH₃ I17(a and b) S —Cl —H —CF₃ I18(a and b)S —Cl —H —OCH₃ I19(a and b) S —Cl —H —OCH₂CH₃ I20(a and b) S —Cl —H—OCF₃ I21(a and b) S —Cl —H -tert-butyl I22(a and b) S —Cl —H-iso-propyl I23(a and b) S —CH₃ —Cl —H I24(a and b) S —CH₃ —Br —H I25(aand b) S —CH₃ —F —H I26(a and b) S —CH₃ —CH₃ —H I27(a and b) S —CH₃ —CF₃—H I28(a and b) S —CH₃ —OCH₃ —H I29(a and b) S —CH₃ —OCH₂CH₃ —H I30(aand b) S —CH₃ —OCF₃ —H I31(a and b) S —CH₃ -tert-butyl —H I32(a and b) S—CH₃ -iso-propyl —H I33(a and b) S —CH₃ —CH₃ —CH₃ I34(a and b) S —CH₃ —H—H I35(a and b) S —CH₃ —H —Cl I36(a and b) S —CH₃ —H —Br I37(a and b) S—CH₃ —H —F I38(a and b) S —CH₃ —H —CH₃ I39(a and b) S —CH₃ —H —CF₃ I40(aand b) S —CH₃ —H —OCH₃ I41(a and b) S —CH₃ —H —OCH₂CH₃ I42(a and b) S—CH₃ —H —OCF₃ I43(a and b) S —CH₃ —H -tert-butyl I44(a and b) S —CH₃ —H-iso-propyl I45(a and b) S —CF₃ —Cl —H I46(a and b) S —CF₃ —Br —H I47(aand b) S —CF₃ —F —H I48(a and b) S —CF₃ —CH₃ —H I49(a and b) S —CF₃ —CF₃—H I50(a and b) S —CF₃ —OCH₃ —H I51(a and b) S —CF₃ —OCH₂CH₃ —H I52(aand b) S —CF₃ —OCF₃ —H I53(a and b) S —CF₃ -tert-butyl —H I54(a and b) S—CF₃ -iso-propyl —H I55(a and b) S —CF₃ —CH₃ —CH₃ I56(a and b) S —CF₃ —H—H I57(a and b) S —CF₃ —H —Cl I58(a and b) S —CF₃ —H —Br I59(a and b) S—CF₃ —H —F I60(a and b) S —CF₃ —H —CH₃ I61(a and b) S —CF₃ —H —CF₃ I62(aand b) S —CF₃ —H —OCH₃ I63(a and b) S —CF₃ —H —OCH₂CH₃ I64(a and b) S—CF₃ —H —OCF₃ I65(a and b) S —CF₃ —H -tert-butyl I66(a and b) S —CF₃ —H-iso-propyl I67(a and b) S —CHF₂ —Cl —H I68(a and b) S —CHF₂ —Br —HI69(a and b) S —CHF₂ —F —H I70(a and b) S —CHF₂ —CH₃ —H I71(a and b) S—CHF₂ —CF₃ —H I72(a and b) S —CHF₂ —OCH₃ —H I73(a and b) S —CHF₂—OCH₂CH₃ —H I74(a and b) S —CHF₂ —OCF₃ —H I75(a and b) S —CHF₂-tert-butyl —H I76(a and b) S —CHF₂ -iso-propyl —H I77(a and b) S —CHF₂—CH₃ —CH₃ I78(a and b) S —CHF₂ —H —H I79(a and b) S —CHF₂ —H —Cl I80(aand b) S —CHF₂ —H —Br I81(a and b) S —CHF₂ —H —F I82(a and b) S —CHF₂ —H—CH₃ I83(a and b) S —CHF₂ —H —CF₃ I84(a and b) S —CHF₂ —H —OCH₃ I85(aand b) S —CHF₂ —H —OCH₂CH₃ I86(a and b) S —CHF₂ —H —OCF₃ I87(a and b) S—CHF₂ —H -tert-butyl I88(a and b) S —CHF₂ —H -iso-propyl I89(a and b) S—Br —Br —H I90(a and b) S —Br —Cl —H I91(a and b) S —Br —F —H I92(a andb) S —Br —CH₃ —H I93(a and b) S —Br —CF₃ —H I94(a and b) S —Br —OCH₃ —HI95(a and b) S —Br —OCH₂CH₃ —H I96(a and b) S —Br —OCF₃ —H I97(a and b)S —Br -tert-butyl —H I98(a and b) S —Br -iso-propyl —H I99(a and b) S—Br —CH₃ —CH₃ I100(a and b) S —Br —H —H I101(a and b) S —Br —H —ClI102(a and b) S —Br —H —Br I103(a and b) S —Br —H —F I104(a and b) S —Br—H —CH₃ I105(a and b) S —Br —H —CF₃ I106(a and b) S —Br —H —OCH₃ I107(aand b) S —Br —H —OCH₂CH₃ I108(a and b) S —Br —H —OCF₃ I109(a and b) S—Br —H -tert-butyl I110(a and b) S —Br —H -iso-propyl I111(a and b) S —I—Cl —H I112(a and b) S —I —Br —H I113(a and b) S —I —F —H I114(a and b)S —I —CH₃ —H I115(a and b) S —I —CF₃ —H I116(a and b) S —I —OCH₃ —HI117(a and b) S —I —OCH₂CH₃ —H I118(a and b) S —I —OCF₃ —H I119(a and b)S —I -tert-butyl —H I120(a and b) S —I -iso-propyl —H I121(a and b) S —I—CH₃ —CH₃ I122(a and b) S —I —H —H I123(a and b) S —I —H —Cl I124(a andb) S —I —H —Br I125(a and b) S —I —H —F I126(a and b) S —I —H —CH₃I127(a and b) S —I —H —CF₃ I128(a and b) S —I —H —OCH₃ I129(a and b) S—I —H —OCH₂CH₃ I130(a and b) S —I —H —OCF₃ I131(a and b) S —I —H-tert-butyl I132(a and b) S —I —H -iso-propyl I133(a and b) O —Cl —Cl —HI134(a and b) O —Cl —Br —H I135(a and b) O —Cl —F —H I136(a and b) O —Cl—CH₃ —H I137(a and b) O —Cl —CF₃ —H I138(a and b) O —Cl —OCH₃ —H I139(aand b) O —Cl —OCH₂CH₃ —H I140(a and b) O —Cl —OCF₃ —H I141(a and b) O—Cl -tert-butyl —H I142(a and b) O —Cl -iso-propyl —H I143(a and b) O—Cl —CH₃ —CH₃ I144(a and b) O —Cl —H —H I145(a and b) O —Cl —H —CH₃I146(a and b) O —Cl —H —Cl I147(a and b) O —Cl —H —Br I148(a and b) O—Cl —H —F I149(a and b) O —Cl —H —CF₃ I150(a and b) O —Cl —H —OCH₃I151(a and b) O —Cl —H —OCH₂CH₃ I152(a and b) O —Cl —H —OCF₃ I153(a andb) O —Cl —H -tert-butyl I154(a and b) O —Cl —H -iso-propyl I155(a and b)O —CH₃ —Cl —H I156(a and b) O —CH₃ —Br —H I157(a and b) O —CH₃ —F —HI158(a and b) O —CH₃ —CH₃ —H I159(a and b) O —CH₃ —CF₃ —H I160(a and b)O —CH₃ —OCH₃ —H I161(a and b) O —CH₃ —OCH₂CH₃ —H I162(a and b) O —CH₃—OCF₃ —H I163(a and b) O —CH₃ -tert-butyl —H I164(a and b) O —CH₃-iso-propyl —H I165(a and b) O —CH₃ —CH₃ —CH₃ I166(a and b) O —CH₃ —H —HI167(a and b) O —CH₃ —H —Cl I168(a and b) O —CH₃ —H —Br I169(a and b) O—CH₃ —H —F I170(a and b) O —CH₃ —H —CH₃ I171(a and b) O —CH₃ —H —CF₃I172(a and b) O —CH₃ —H —OCH₃ I173(a and b) O —CH₃ —H —OCH₂CH₃ I174(aand b) O —CH₃ —H —OCF₃ I175(a and b) O —CH₃ —H -tert-butyl I176(a and b)O —CH₃ —H -iso-propyl I177(a and b) O —CF₃ —Cl —H I178(a and b) O —CF₃—Br —H I179(a and b) O —CF₃ —F —H I180(a and b) O —CF₃ —CH₃ —H I181(aand b) O —CF₃ —CF₃ —H I182(a and b) O —CF₃ —OCH₃ —H I183(a and b) O —CF₃—OCH₂CH₃ —H I184(a and b) O —CF₃ —OCF₃ —H I185(a and b) O —CF₃-tert-butyl —H I186(a and b) O —CF₃ -iso-propyl —H I187(a and b) O —CF₃—CH₃ —CH₃ I188(a and b) O —CF₃ —H —H I189(a and b) O —CF₃ —H —Cl I190(aand b) O —CF₃ —H —Br I191(a and b) O —CF₃ —H —F I192(a and b) O —CF₃ —H—CH₃ I193(a and b) O —CF₃ —H —CF₃ I194(a and b) O —CF₃ —H —OCH₃ I195(aand b) O —CF₃ —H —OCH₂CH₃ I196(a and b) O —CF₃ —H —OCF₃ I197(a and b) O—CF₃ —H -tert-butyl I198(a and b) O —CF₃ —H -iso-propyl I199(a and b) O—CHF₂ —Cl —H I200(a and b) O —CHF₂ —Br —H I201(a and b) O —CHF₂ —F —HI202(a and b) O —CHF₂ —CH₃ —H I203(a and b) O —CHF₂ —CF₃ —H I204(a andb) O —CHF₂ —OCH₃ —H I205(a and b) O —CHF₂ —OCH₂CH₃ —H I206(a and b) O—CHF₂ —OCF₃ —H I207(a and b) O —CHF₂ -tert-butyl —H I208(a and b) O—CHF₂ -iso-propyl —H I209(a and b) O —CHF₂ —CH₃ —CH₃ I210(a and b) O—CHF₂ —H —H I211(a and b) O —CHF₂ —H —Cl I212(a and b) O —CHF₂ —H —BrI213(a and b) O —CHF₂ —H —F I214(a and b) O —CHF₂ —H —CH₃ I215(a and b)O —CHF₂ —H —CF₃ I216(a and b) O —CHF₂ —H —OCH₃ I217(a and b) O —CHF₂ —H—OCH₂CH₃ I218(a and b) O —CHF₂ —H —OCF₃ I219(a and b) O —CHF₂ —H-tert-butyl I220(a and b) O —CHF₂ —H -iso-propyl I221(a and b) O —Br —Br—H I222(a and b) O —Br —Cl —H I223(a and b) O —Br —F —H I224(a and b) O—Br —CH₃ —H I225(a and b) O —Br —CF₃ —H I226(a and b) O —Br —OCH₃ —HI227(a and b) O —Br —OCH₂CH₃ —H I228(a and b) O —Br —OCF₃ —H I229(a andb) O —Br -tert-butyl —H I230(a and b) O —Br -iso-propyl —H I231(a and b)O —Br —CH₃ —CH₃ I232(a and b) O —Br —H —H I233(a and b) O —Br —H —ClI234(a and b) O —Br —H —Br I235(a and b) O —Br —H —F I236(a and b) O —Br—H —CH₃ I237(a and b) O —Br —H —CF₃ I238(a and b) O —Br —H —OCH₃ I239(aand b) O —Br —H —OCH₂CH₃ I240(a and b) O —Br —H —OCF₃ I241(a and b) O—Br —H -tert-butyl I242(a and b) O —Br —H -iso-propyl I243(a and b) O —I—Cl —H I244(a and b) O —I —Br —H I245(a and b) O —I —F —H I246(a and b)O —I —CH₃ —H I247(a and b) O —I —CF₃ —H I248(a and b) O —I —OCH₃ —HI249(a and b) O —I —OCH₂CH₃ —H I250(a and b) O —I —OCF₃ —H I251(a and b)O —I -tert-butyl —H I252(a and b) O —I -iso-propyl —H I253(a and b) O —I—CH₃ —CH₃ I254(a and b) O —I —H —H I255(a and b) O —I —H —Cl I256(a andb) O —I —H —Br I257(a and b) O —I —H —F I258(a and b) O —I —H —CH₃I259(a and b) O —I —H —CF₃ I260(a and b) O —I —H —OCH₃ I261(a and b) O—I —H —OCH₂CH₃ I262(a and b) O —I —H —OCF₃ I263(a and b) O —I —H-tert-butyl I264(a and b) O —I —H -iso-propyl I265(a and b) NH —Cl —Cl—H I266(a and b) NH —Cl —Br —H I267(a and b) NH —Cl —F —H I268(a and b)NH —Cl —CH₃ —H I269(a and b) NH —Cl —CF₃ —H I270(a and b) NH —Cl —OCH₃—H I271(a and b) NH —Cl —OCH₂CH₃ —H I272(a and b) NH —Cl —OCF₃ —H I273(aand b) NH —Cl -tert-butyl —H I274(a and b) NH —Cl -iso-propyl —H I275(aand b) NH —Cl —CH₃ —CH₃ I276(a and b) NH —Cl —H —H I277(a and b) NH —Cl—H —CH₃ I278(a and b) NH —Cl —H —Cl I279(a and b) NH —Cl —H —Br I280(aand b) NH —Cl —H —F I281(a and b) NH —Cl —H —CF₃ I282(a and b) NH —Cl —H—OCH₃ I283(a and b) NH —Cl —H —OCH₂CH₃ I284(a and b) NH —Cl —H —OCF₃I285(a and b) NH —Cl —H -tert-butyl I286(a and b) NH —Cl —H -iso-propylI287(a and b) NH —CH₃ —Cl —H I288(a and b) NH —CH₃ —Br —H I289(a and b)NH —CH₃ —F —H I290(a and b) NH —CH₃ —CH₃ —H I291(a and b) NH —CH₃ —CF₃—H I292(a and b) NH —CH₃ —OCH₃ —H I293(a and b) NH —CH₃ —OCH₂CH₃ —HI294(a and b) NH —CH₃ —OCF₃ —H I295(a and b) NH —CH₃ -tert-butyl —HI296(a and b) NH —CH₃ -iso-propyl —H I297(a and b) NH —CH₃ —CH₃ —CH₃I298(a and b) NH —CH₃ —H —H I299(a and b) NH —CH₃ —H —Cl I300(a and b)NH —CH₃ —H —Br I301(a and b) NH —CH₃ —H —F I302(a and b) NH —CH₃ —H —CH₃I303(a and b) NH —CH₃ —H —CF₃ I304(a and b) NH —CH₃ —H —OCH₃ I305(a andb) NH —CH₃ —H —OCH₂CH₃ I306(a and b) NH —CH₃ —H —OCF₃ I307(a and b) NH—CH₃ —H -tert-butyl I308(a and b) NH —CH₃ —H -iso-propyl I309(a and b)NH —CF₃ —Cl —H I310(a and b) NH —CF₃ —Br —H I311(a and b) NH —CF₃ —F —HI312(a and b) NH —CF₃ —CH₃ —H I313(a and b) NH —CF₃ —CF₃ —H I314(a andb) NH —CF₃ —OCH₃ —H I315(a and b) NH —CF₃ —OCH₂CH₃ —H I316(a and b) NH—CF₃ —OCF₃ —H I317(a and b) NH —CF₃ -tert-butyl —H I318(a and b) NH —CF₃-iso-propyl —H I319(a and b) NH —CF₃ —CH₃ —CH₃ I320(a and b) NH —CF₃ —H—H I321(a and b) NH —CF₃ —H —Cl I322(a and b) NH —CF₃ —H —Br I323(a andb) NH —CF₃ —H —F I324(a and b) NH —CF₃ —H —CH₃ I325(a and b) NH —CF₃ —H—CF₃ I326(a and b) NH —CF₃ —H —OCH₃ I327(a and b) NH —CF₃ —H —OCH₂CH₃I328(a and b) NH —CF₃ —H —OCF₃ I329(a and b) NH —CF₃ —H -tert-butylI330(a and b) NH —CF₃ —H -iso-propyl I331(a and b) NH —CHF₂ —Cl —HI332(a and b) NH —CHF₂ —Br —H I333(a and b) NH —CHF₂ —F —H I334(a and b)NH —CHF₂ —CH₃ —H I335(a and b) NH —CHF₂ —CF₃ —H I336(a and b) NH —CHF₂—OCH₃ —H I337(a and b) NH —CHF₂ —OCH₂CH₃ —H I338(a and b) NH —CHF₂ —OCF₃—H I339(a and b) NH —CHF₂ -tert-butyl —H I340(a and b) NH —CHF₂-iso-propyl —H I341(a and b) NH —CHF₂ —CH₃ —CH₃ I342(a and b) NH —CHF₂—H —H I343(a and b) NH —CHF₂ —H —Cl I344(a and b) NH —CHF₂ —H —Br I345(aand b) NH —CHF₂ —H —F I346(a and b) NH —CHF₂ —H —CH₃ I347(a and b) NH—CHF₂ —H —CF₃ I348(a and b) NH —CHF₂ —H —OCH₃ I349(a and b) NH —CHF₂ —H—OCH₂CH₃ I350(a and b) NH —CHF₂ —H —OCF₃ I351(a and b) NH —CHF₂ —H-tert-butyl I352(a and b) NH —CHF₂ —H -iso-propyl I353(a and b) NH —Br—Br —H I354(a and b) NH —Br —Cl —H I355(a and b) NH —Br —F —H I356(a andb) NH —Br —CH₃ —H I357(a and b) NH —Br —CF₃ —H I358(a and b) NH —Br—OCH₃ —H I359(a and b) NH —Br —OCH₂CH₃ —H I360(a and b) NH —Br —OCF₃ —HI361(a and b) NH —Br -tert-butyl —H I362(a and b) NH —Br -iso-propyl —HI363(a and b) NH —Br —CH₃ —CH₃ I364(a and b) NH —Br —H —H I365(a and b)NH —Br —H —Cl I366(a and b) NH —Br —H —Br I367(a and b) NH —Br —H —FI368(a and b) NH —Br —H —CH₃ I369(a and b) NH —Br —H —CF₃ I370(a and b)NH —Br —H —OCH₃ I371(a and b) NH —Br —H —OCH₂CH₃ I372(a and b) NH —Br —H—OCF₃ I373(a and b) NH —Br —H -tert-butyl I374(a and b) NH —Br —H-iso-propyl I375(a and b) NH —I —Cl —H I376(a and b) NH —I —Br —H I377(aand b) NH —I —F —H I378(a and b) NH —I —CH₃ —H I379(a and b) NH —I —CF₃—H I380(a and b) NH —I —OCH₃ —H I381(a and b) NH —I —OCH₂CH₃ —H I382(aand b) NH —I —OCF₃ —H I383(a and b) NH —I -tert-butyl —H I384(a and b)NH —I -iso-propyl —H I385(a and b) NH —I —CH₃ —CH₃ I386(a and b) NH —I—H —H I387(a and b) NH —I —H —Cl I388(a and b) NH —I —H —Br I389(a andb) NH —I —H —F I390(a and b) NH —I —H —CH₃ I391(a and b) NH —I —H —CF₃I392(a and b) NH —I —H —OCH₃ I393(a and b) NH —I —H —OCH₂CH₃ I394(a andb) NH —I —H —OCF₃ I395(a and b) NH —I —H -tert-butyl I396(a and b) NH —I—H -iso-propyl In the column labeled “Compound”: (a) means Z₁ is CH andZ₂ is N; and (b) means Z₁ is N and Z₂ is CH.

TABLE 10 (XII)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) J1(a and b) S —Cl —Cl —H J2(a and b) S —Cl —Br —H J3(aand b) S —Cl —F —H J4(a and b) S —Cl —CH₃ —H J5(a and b) S —Cl —CF₃ —HJ6(a and b) S —Cl —OCH₃ —H J7(a and b) S —Cl —OCH₂CH₃ —H J8(a and b) S—Cl —OCF₃ —H J9(a and b) S —Cl -tert-butyl —H J10(a and b) S —Cl-iso-propyl —H J11(a and b) S —Cl —CH₃ —CH₃ J12(a and b) S —Cl —H —HJ13(a and b) S —Cl —H —Cl J14(a and b) S —Cl —H —Br J15(a and b) S —Cl—H —F J16(a and b) S —Cl —H —CH₃ J17(a and b) S —Cl —H —CF₃ J18(a and b)S —Cl —H —OCH₃ J19(a and b) S —Cl —H —OCH₂CH₃ J20(a and b) S —Cl —H—OCF₃ J21(a and b) S —Cl —H -tert-butyl J22(a and b) S —Cl —H-iso-propyl J23(a and b) S —CH₃ —Cl —H J24(a and b) S —CH₃ —Br —H J25(aand b) S —CH₃ —F —H J26(a and b) S —CH₃ —CH₃ —H J27(a and b) S —CH₃ —CF₃—H J28(a and b) S —CH₃ —OCH₃ —H J29(a and b) S —CH₃ —OCH₂CH₃ —H J30(aand b) S —CH₃ —OCF₃ —H J31(a and b) S —CH₃ -tert-butyl —H J32(a and b) S—CH₃ -iso-propyl —H J33(a and b) S —CH₃ —CH₃ —CH₃ J34(a and b) S —CH₃ —H—H J35(a and b) S —CH₃ —H —Cl J36(a and b) S —CH₃ —H —Br J37(a and b) S—CH₃ —H —F J38(a and b) S —CH₃ —H —CH₃ J39(a and b) S —CH₃ —H —CF₃ J40(aand b) S —CH₃ —H —OCH₃ J41(a and b) S —CH₃ —H —OCH₂CH₃ J42(a and b) S—CH₃ —H —OCF₃ J43(a and b) S —CH₃ —H -tert-butyl J44(a and b) S —CH₃ —H-iso-propyl J45(a and b) S —CF₃ —Cl —H J46(a and b) S —CF₃ —Br —H J47(aand b) S —CF₃ —F —H J48(a and b) S —CF₃ —CH₃ —H J49(a and b) S —CF₃ —CF₃—H J50(a and b) S —CF₃ —OCH₃ —H J51(a and b) S —CF₃ —OCH₂CH₃ —H J52(aand b) S —CF₃ —OCF₃ —H J53(a and b) S —CF₃ -tert-butyl —H J54(a and b) S—CF₃ -iso-propyl —H J55(a and b) S —CF₃ —CH₃ —CH₃ J56(a and b) S —CF₃ —H—H J57(a and b) S —CF₃ —H —Cl J58(a and b) S —CF₃ —H —Br J59(a and b) S—CF₃ —H —F J60(a and b) S —CF₃ —H —CH₃ J61(a and b) S —CF₃ —H —CF₃ J62(aand b) S —CF₃ —H —OCH₃ J63(a and b) S —CF₃ —H —OCH₂CH₃ J64(a and b) S—CF₃ —H —OCF₃ J65(a and b) S —CF₃ —H -tert-butyl J66(a and b) S —CF₃ —H-iso-propyl J67(a and b) S —CHF₂ —Cl —H J68(a and b) S —CHF₂ —Br —HJ69(a and b) S —CHF₂ —F —H J70(a and b) S —CHF₂ —CH₃ —H J71(a and b) S—CHF₂ —CF₃ —H J72(a and b) S —CHF₂ —OCH₃ —H J73(a and b) S —CHF₂—OCH₂CH₃ —H J74(a and b) S —CHF₂ —OCF₃ —H J75(a and b) S —CHF₂-tert-butyl —H J76(a and b) S —CHF₂ -iso-propyl —H J77(a and b) S —CHF₂—CH₃ —CH₃ J78(a and b) S —CHF₂ —H —H J79(a and b) S —CHF₂ —H —Cl J80(aand b) S —CHF₂ —H —Br J81(a and b) S —CHF₂ —H —F J82(a and b) S —CHF₂ —H—CH₃ J83(a and b) S —CHF₂ —H —CF₃ J84(a and b) S —CHF₂ —H —OCH₃ J85(aand b) S —CHF₂ —H —OCH₂CH₃ J86(a and b) S —CHF₂ —H —OCF₃ J87(a and b) S—CHF₂ —H -tert-butyl J88(a and b) S —CHF₂ —H -iso-propyl J89(a and b) S—Br —Br —H J90(a and b) S —Br —Cl —H J91(a and b) S —Br —F —H J92(a andb) S —Br —CH₃ —H J93(a and b) S —Br —CF₃ —H J94(a and b) S —Br —OCH₃ —HJ95(a and b) S —Br —OCH₂CH₃ —H J96(a and b) S —Br —OCF₃ —H J97(a and b)S —Br -tert-butyl —H J98(a and b) S —Br -iso-propyl —H J99(a and b) S—Br —CH₃ —CH₃ J100(a and b) S —Br —H —H J101(a and b) S —Br —H —ClJ102(a and b) S —Br —H —Br J103(a and b) S —Br —H —F J104(a and b) S —Br—H —CH₃ J105(a and b) S —Br —H —CF₃ J106(a and b) S —Br —H —OCH₃ J107(aand b) S —Br —H —OCH₂CH₃ J108(a and b) S —Br —H —OCF₃ J109(a and b) S—Br —H -tert-butyl J110(a and b) S —Br —H -iso-propyl J111(a and b) S —I—Cl —H J112(a and b) S —I —Br —H J113(a and b) S —I —F —H J114(a and b)S —I —CH₃ —H J115(a and b) S —I —CF₃ —H J116(a and b) S —I —OCH₃ —HJ117(a and b) S —I —OCH₂CH₃ —H J118(a and b) S —I —OCF₃ —H J119(a and b)S —I -tert-butyl —H J120(a and b) S —I -iso-propyl —H J121(a and b) S —I—CH₃ —CH₃ J122(a and b) S —I —H —H J123(a and b) S —I —H —Cl J124(a andb) S —I —H —Br J125(a and b) S —I —H —F J126(a and b) S —I —H —CH₃J127(a and b) S —I —H —CF₃ J128(a and b) S —I —H —OCH₃ J129(a and b) S—I —H —OCH₂CH₃ J130(a and b) S —I —H —OCF₃ J131(a and b) S —I —H-tert-butyl J132(a and b) S —I —H -iso-propyl J133(a and b) O —Cl —Cl —HJ134(a and b) O —Cl —Br —H J135(a and b) O —Cl —F —H J136(a and b) O —Cl—CH₃ —H J137(a and b) O —Cl —CF₃ —H J138(a and b) O —Cl —OCH₃ —H J139(aand b) O —Cl —OCH₂CH₃ —H J140(a and b) O —Cl —OCF₃ —H J141(a and b) O—Cl -tert-butyl —H J142(a and b) O —Cl -iso-propyl —H J143(a and b) O—Cl —CH₃ —CH₃ J144(a and b) O —Cl —H —H J145(a and b) O —Cl —H —CH₃J146(a and b) O —Cl —H —Cl J147(a and b) O —Cl —H —Br J148(a and b) O—Cl —H —F J149(a and b) O —Cl —H —CF₃ J150(a and b) O —Cl —H —OCH₃J151(a and b) O —Cl —H —OCH₂CH₃ J152(a and b) O —Cl —H —OCF₃ J153(a andb) O —Cl —H -tert-butyl J154(a and b) O —Cl —H -iso-propyl J155(a and b)O —CH₃ —Cl —H J156(a and b) O —CH₃ —Br —H J157(a and b) O —CH₃ —F —HJ158(a and b) O —CH₃ —CH₃ —H J159(a and b) O —CH₃ —CF₃ —H J160(a and b)O —CH₃ —OCH₃ —H J161(a and b) O —CH₃ —OCH₂CH₃ —H J162(a and b) O —CH₃—OCF₃ —H J163(a and b) O —CH₃ -tert-butyl —H J164(a and b) O —CH₃-iso-propyl —H J165(a and b) O —CH₃ —CH₃ —CH₃ J166(a and b) O —CH₃ —H —HJ167(a and b) O —CH₃ —H —Cl J168(a and b) O —CH₃ —H —Br J169(a and b) O—CH₃ —H —F J170(a and b) O —CH₃ —H —CH₃ J171(a and b) O —CH₃ —H —CF₃J172(a and b) O —CH₃ —H —OCH₃ J173(a and b) O —CH₃ —H —OCH₂CH₃ J174(aand b) O —CH₃ —H —OCF₃ J175(a and b) O —CH₃ —H -tert-butyl J176(a and b)O —CH₃ —H -iso-propyl J177(a and b) O —CF₃ —Cl —H J178(a and b) O —CF₃—Br —H J179(a and b) O —CF₃ —F —H J180(a and b) O —CF₃ —CH₃ —H J181(aand b) O —CF₃ —CF₃ —H J182(a and b) O —CF₃ —OCH₃ —H J183(a and b) O —CF₃—OCH₂CH₃ —H J184(a and b) O —CF₃ —OCF₃ —H J185(a and b) O —CF₃-tert-butyl —H J186(a and b) O —CF₃ -iso-propyl —H J187(a and b) O —CF₃—CH₃ —CH₃ J188(a and b) O —CF₃ —H —H J189(a and b) O —CF₃ —H —Cl J190(aand b) O —CF₃ —H —Br J191(a and b) O —CF₃ —H —F J192(a and b) O —CF₃ —H—CH₃ J193(a and b) O —CF₃ —H —CF₃ J194(a and b) O —CF₃ —H —OCH₃ J195(aand b) O —CF₃ —H —OCH₂CH₃ J196(a and b) O —CF₃ —H —OCF₃ J197(a and b) O—CF₃ —H -tert-butyl J198(a and b) O —CF₃ —H -iso-propyl J199(a and b) O—CHF₂ —Cl —H J200(a and b) O —CHF₂ —Br —H J201(a and b) O —CHF₂ —F —HJ202(a and b) O —CHF₂ —CH₃ —H J203(a and b) O —CHF₂ —CF₃ —H J204(a andb) O —CHF₂ —OCH₃ —H J205(a and b) O —CHF₂ —OCH₂CH₃ —H J206(a and b) O—CHF₂ —OCF₃ —H J207(a and b) O —CHF₂ -tert-butyl —H J208(a and b) O—CHF₂ -iso-propyl —H J209(a and b) O —CHF₂ —CH₃ —CH₃ J210(a and b) O—CHF₂ —H —H J211(a and b) O —CHF₂ —H —Cl J212(a and b) O —CHF₂ —H —BrJ213(a and b) O —CHF₂ —H —F J214(a and b) O —CHF₂ —H —CH₃ J215(a and b)O —CHF₂ —H —CF₃ J216(a and b) O —CHF₂ —H —OCH₃ J217(a and b) O —CHF₂ —H—OCH₂CH₃ J218(a and b) O —CHF₂ —H —OCF₃ J219(a and b) O —CHF₂ —H-tert-butyl J220(a and b) O —CHF₂ —H -iso-propyl J221(a and b) O —Br —Br—H J222(a and b) O —Br —Cl —H J223(a and b) O —Br —F —H J224(a and b) O—Br —CH₃ —H J225(a and b) O —Br —CF₃ —H J226(a and b) O —Br —OCH₃ —HJ227(a and b) O —Br —OCH₂CH₃ —H J228(a and b) O —Br —OCF₃ —H J229(a andb) O —Br -tert-butyl —H J230(a and b) O —Br -iso-propyl —H J231(a and b)O —Br —CH₃ —CH₃ J232(a and b) O —Br —H —H J233(a and b) O —Br —H —ClJ234(a and b) O —Br —H —Br J235(a and b) O —Br —H —F J236(a and b) O —Br—H —CH₃ J237(a and b) O —Br —H —CF₃ J238(a and b) O —Br —H —OCH₃ J239(aand b) O —Br —H —OCH₂CH₃ J240(a and b) O —Br —H —OCF₃ J241(a and b) O—Br —H -tert-butyl J242(a and b) O —Br —H -iso-propyl J243(a and b) O —I—Cl —H J244(a and b) O —I —Br —H J245(a and b) O —I —F —H J246(a and b)O —I —CH₃ —H J247(a and b) O —I —CF₃ —H J248(a and b) O —I —OCH₃ —HJ249(a and b) O —I —OCH₂CH₃ —H J250(a and b) O —I —OCF₃ —H J251(a and b)O —I -tert-butyl —H J252(a and b) O —I -iso-propyl —H J253(a and b) O —I—CH₃ —CH₃ J254(a and b) O —I —H —H J255(a and b) O —I —H —Cl J256(a andb) O —I —H —Br J257(a and b) O —I —H —F J258(a and b) O —I —H —CH₃J259(a and b) O —I —H —CF₃ J260(a and b) O —I —H —OCH₃ J261(a and b) O—I —H —OCH₂CH₃ J262(a and b) O —I —H —OCF₃ J263(a and b) O —I —H-tert-butyl J264(a and b) O —I —H -iso-propyl J265(a and b) NH —Cl —Cl—H J266(a and b) NH —Cl —Br —H J267(a and b) NH —Cl —F —H J268(a and b)NH —Cl —CH₃ —H J269(a and b) NH —Cl —CF₃ —H J270(a and b) NH —Cl —OCH₃—H J271(a and b) NH —Cl —OCH₂CH₃ —H J272(a and b) NH —Cl —OCF₃ —H J273(aand b) NH —Cl -tert-butyl —H J274(a and b) NH —Cl -iso-propyl —H J275(aand b) NH —Cl —CH₃ —CH₃ J276(a and b) NH —Cl —H —H J277(a and b) NH —Cl—H —CH₃ J278(a and b) NH —Cl —H —Cl J279(a and b) NH —Cl —H —Br J280(aand b) NH —Cl —H —F J281(a and b) NH —Cl —H —CF₃ J282(a and b) NH —Cl —H—OCH₃ J283(a and b) NH —Cl —H —OCH₂CH₃ J284(a and b) NH —Cl —H —OCF₃J285(a and b) NH —Cl —H -tert-butyl J286(a and b) NH —Cl —H -iso-propylJ287(a and b) NH —CH₃ —Cl —H J288(a and b) NH —CH₃ —Br —H J289(a and b)NH —CH₃ —F —H J290(a and b) NH —CH₃ —CH₃ —H J291(a and b) NH —CH₃ —CF₃—H J292(a and b) NH —CH₃ —OCH₃ —H J293(a and b) NH —CH₃ —OCH₂CH₃ —HJ294(a and b) NH —CH₃ —OCF₃ —H J295(a and b) NH —CH₃ -tert-butyl —HJ296(a and b) NH —CH₃ -iso-propyl —H J297(a and b) NH —CH₃ —CH₃ —CH₃J298(a and b) NH —CH₃ —H —H J299(a and b) NH —CH₃ —H —Cl J300(a and b)NH —CH₃ —H —Br J301(a and b) NH —CH₃ —H —F J302(a and b) NH —CH₃ —H —CH₃J303(a and b) NH —CH₃ —H —CF₃ J304(a and b) NH —CH₃ —H —OCH₃ J305(a andb) NH —CH₃ —H —OCH₂CH₃ J306(a and b) NH —CH₃ —H —OCF₃ J307(a and b) NH—CH₃ —H -tert-butyl J308(a and b) NH —CH₃ —H -iso-propyl J309(a and b)NH —CF₃ —Cl —H J310(a and b) NH —CF₃ —Br —H J311(a and b) NH —CF₃ —F —HJ312(a and b) NH —CF₃ —CH₃ —H J313(a and b) NH —CF₃ —CF₃ —H J314(a andb) NH —CF₃ —OCH₃ —H J315(a and b) NH —CF₃ —OCH₂CH₃ —H J316(a and b) NH—CF₃ —OCF₃ —H J317(a and b) NH —CF₃ -tert-butyl —H J318(a and b) NH —CF₃-iso-propyl —H J319(a and b) NH —CF₃ —CH₃ —CH₃ J320(a and b) NH —CF₃ —H—H J321(a and b) NH —CF₃ —H —Cl J322(a and b) NH —CF₃ —H —Br J323(a andb) NH —CF₃ —H —F J324(a and b) NH —CF₃ —H —CH₃ J325(a and b) NH —CF₃ —H—CF₃ J326(a and b) NH —CF₃ —H —OCH₃ J327(a and b) NH —CF₃ —H —OCH₂CH₃J328(a and b) NH —CF₃ —H —OCF₃ J329(a and b) NH —CF₃ —H -tert-butylJ330(a and b) NH —CF₃ —H -iso-propyl J331(a and b) NH —CHF₂ —Cl —HJ332(a and b) NH —CHF₂ —Br —H J333(a and b) NH —CHF₂ —F —H J334(a and b)NH —CHF₂ —CH₃ —H J335(a and b) NH —CHF₂ —CF₃ —H J336(a and b) NH —CHF₂—OCH₃ —H J337(a and b) NH —CHF₂ —OCH₂CH₃ —H J338(a and b) NH —CHF₂ —OCF₃—H J339(a and b) NH —CHF₂ -tert-butyl —H J340(a and b) NH —CHF₂-iso-propyl —H J341(a and b) NH —CHF₂ —CH₃ —CH₃ J342(a and b) NH —CHF₂—H —H J343(a and b) NH —CHF₂ —H —Cl J344(a and b) NH —CHF₂ —H —Br J345(aand b) NH —CHF₂ —H —F J346(a and b) NH —CHF₂ —H —CH₃ J347(a and b) NH—CHF₂ —H —CF₃ J348(a and b) NH —CHF₂ —H —OCH₃ J349(a and b) NH —CHF₂ —H—OCH₂CH₃ J350(a and b) NH —CHF₂ —H —OCF₃ J351(a and b) NH —CHF₂ —H-tert-butyl J352(a and b) NH —CHF₂ —H -iso-propyl J353(a and b) NH —Br—Br —H J354(a and b) NH —Br —Cl —H J355(a and b) NH —Br —F —H J356(a andb) NH —Br —CH₃ —H J357(a and b) NH —Br —CF₃ —H J358(a and b) NH —Br—OCH₃ —H J359(a and b) NH —Br —OCH₂CH₃ —H J360(a and b) NH —Br —OCF₃ —HJ361(a and b) NH —Br -tert-butyl —H J362(a and b) NH —Br -iso-propyl —HJ363(a and b) NH —Br —CH₃ —CH₃ J364(a and b) NH —Br —H —H J365(a and b)NH —Br —H —Cl J366(a and b) NH —Br —H —Br J367(a and b) NH —Br —H —FJ368(a and b) NH —Br —H —CH₃ J369(a and b) NH —Br —H —CF₃ J370(a and b)NH —Br —H —OCH₃ J371(a and b) NH —Br —H —OCH₂CH₃ J372(a and b) NH —Br —H—OCF₃ J373(a and b) NH —Br —H -tert-butyl J374(a and b) NH —Br —H-iso-propyl J375(a and b) NH —I —Cl —H J376(a and b) NH —I —Br —H J377(aand b) NH —I —F —H J378(a and b) NH —I —CH₃ —H J379(a and b) NH —I —CF₃—H J380(a and b) NH —I —OCH₃ —H J381(a and b) NH —I —OCH₂CH₃ —H J382(aand b) NH —I —OCF₃ —H J383(a and b) NH —I -tert-butyl —H J384(a and b)NH —I -iso-propyl —H J385(a and b) NH —I —CH₃ —CH₃ J386(a and b) NH —I—H —H J387(a and b) NH —I —H —Cl J388(a and b) NH —I —H —Br J389(a andb) NH —I —H —F J390(a and b) NH —I —H —CH₃ J391(a and b) NH —I —H —CF₃J392(a and b) NH —I —H —OCH₃ J393(a and b) NH —I —H —OCH₂CH₃ J394(a andb) NH —I —H —OCF₃ J395(a and b) NH —I —H -tert-butyl J396(a and b) NH —I—H -iso-propyl In the column labeled “Compound”: (a) means Z₁ is CH andZ₂ is N; and (b) means Z₁ is N and Z₂ is CH.

4.4 Definitions

As used in connection with the Pyridylene Compounds herein, the termsused above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.Representative branched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl,3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl 1-butenyl,-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl, and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₈-C₁₄)bicycloalkyls include -indanyl,-1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl,-perhydronaphthyl and the like.

“—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated cyclic alkylring. Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl,-1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl-aceanthreneyl,-1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl,-perhydrophenanthrenyl and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls include-indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,-1,2,7,8-tetrahydronaphthalenyl and the like.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl and the like.

“—(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, a 5-membered heterocyclecan contain up to 4 heteroatoms, a 6-membered heterocycle can contain upto 6 heteroatoms, and a 7-membered heterocycle can contain up to 7heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 7-membered)heterocycle can be attached via anitrogen or carbon atom. Representative (3- to 7-membered)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, and a 5-memberedheterocycle can contain up to 4 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(3- to5-membered)heterocycle can be attached via a nitrogen or carbon atom.Representative -(3- to 5-membered)heterocycles include furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyland the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl and the like.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidyl, pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl,phthalazinyl, and quinazolinyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCl, —CHClI, and—CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —CI₃.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

The phrase “pyridyl group” means

where R₁, R₂, and n are defined above for the Pyridylene Compounds offormula (I) and (II).

The phrase “pyrazinyl group” means,

where R₁, R₂, and p are defined above for the Pyridylene Compounds offormula (I) and (II).

The phrase “pyrimidinyl group” means

where R₁, R₂, and p are defined above for the Pyridylene Compounds offormula (I) and (II).

The phrase “pyridazinyl group” means

where R₁, R₂, and p are defined above for the Pyridylene Compounds offormula (I) and (II).

The phrase “thiadiazolyl group” means

where R₁ is defined above for the Pyridylene Compounds of formula (I)and (II).

The phrase “benzoimidiazolyl group” means

where R₈ and s are defined above for the Pyridylene Compounds of formula(I) and (II).

The phrase “benzothiazolyl group” means

where R₈ and s are defined above for the Pyridylene Compounds of formula(I) and (II).

The phrase “benzooxazolyl group” means

where R₈ and s are defined above for the Pyridylene Compounds of formula(I) and (II).

The phrase “pyridylene ring” in connection with the Pyridylene Compoundsof formula (I) means

where R₃ and m are defined above for the Pyridylene Compounds of formula(I) and (II) and the numbers designate the position of each atom of thepyridylene ring of formula (I).

The phrase “pyridylene ring” in connection with the Pyridylene Compoundsof formula (II) means

where R₃ and m are defined above for the Pyridylene Compounds of formula(I) and (II) and the numbers designate the position of each atom of thepyridylene ring of formula (II).

The term “animal” includes, but is not limited to, a cow, monkey,baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig, and human.

The phrase “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from a PyridyleneCompound including a salt formed from an acid and a basic functionalgroup, such as a nitrogen group, of one of the Pyridylene Compounds.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucoronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also includes a salt prepared from aPyridylene Compound having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine and the like.

The phrase “effective amount,” when used in connection with a PyridyleneCompound means an amount effective for: (a) treating or preventing aCondition; or (b) inhibiting VR1, mGluR1, or mGluR5 function in a cell.

The phrase “effective amount,” when used in connection with the anothertherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, the number of second groups is one or two.

In another embodiment, the number of second groups is one.

The term “THF” means tetrahydrofuran.

The term “DMF” means dimethylformamide.

The term “HOBT” means 1-hydroxybenzotriazole hydrate.

The term “EDCI” means 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrases “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasingthe overall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof.

4.5 Methods for Making the Pyridylene Compounds

The Pyridylene Compounds can be made using conventional organicsynthesis or by the following illustrative methods shown in the schemesbelow.

4.5.1 Methods for Making the Pyridylene Compounds of Formula (I) where Xis O

The Pyridylene Compounds of formula (I) where X is O can be obtained bythe following illustrative method shown below in Scheme 1.

where Ar₂, R₁, R₂, R₃, m, n, and p are defined above; Y is a halogen;and either Z₁ is N and Z₂ is CH or Z₁ is CH and Z₂ is N.

To a solution of a halogenated benzoic acid 1 in DMF (0.33 M) is addedabout 1.1 equivalents of amine, Ar₂—NH₂, and the resulting solution isallowed to stir for about min at a temperature of about 25° C. To theresulting solution is then added about 0.5 equivalent of HOBT and about1 equivalent of EDCI and the resulting mixture is allowed to stir forabout 2 h at about 25° C. The reaction mixture is then diluted withabout 100 mL 2N aqueous sodium hydroxide and extracted with ethylacetate (3 extractions, about 100 mL/extraction). The ethyl acetatelayers are combined and the ethyl acetate is removed under reducedpressure to provide a compound of formula 2. The compound of formula 2is dissolved in DMF (0.04M) and about 3 equivalents of zinc bromide 3a-eand about 0.05 equivalents of Pd(PPh₃)₄ are added to the suspensionunder a nitrogen atmosphere. The resulting reaction mixture is allowedto stir for about 2 h at a temperature of about 100° C. The solvent isthen removed under reduced pressure to provide a Pyridylene Compoundwhere X is O. The Pyridylene Compound where X is O can be purified bymeans known to those skilled in the art. Representative methods topurify the Pyridylene Compound where X is O include, but are not limitedto column chromatography, preparative thin-layer chromatography,preparative high pressure liquid chromatography (HPLC), andrecrystallization.

If the compound of formula 2 is substituted with a hydroxyl or aminogroup, the hydroxyl or amino group is protected using a suitableprotecting group before being reacted with zinc bromide 3a-e. Similarly,if R₂ is a hydroxyl or amino group, the hydroxyl or amino group isprotected before forming the zinc bromide reagent. Suitable protectinggroups for hydroxyl group include, but are not limited to, methyl ether,methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethylether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether,tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether,methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether,tetrahydrothiofuranyl ether, 1-ethoxyethyl ether,1-methyl-1-methoxyethyl ether, 2-(phenylselenyl ether), tert-butylether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethylether, o-napthyldiphenylmethyl ether, p-methoxydiphenylmethyl ether,9-(9-phenyl-10-oxo)anthryl ether (tritylone), trimethylsilyl ether,iso-propyldimethylsilyl ether, tert-butyldimethylsilyl ether,tert-butyldiphenylsilyl ether, tribenzylsilyl ether, tri-iso-propylsilylether, formate ester, acetate ester, trichloroacetate ester,phenoxyacetate ester, iso-butyrate ester, pivaloate ester, adamantoateester, benzoate ester, 2,4,6-trimethyl (mesitoate) ester, methylcarbonate, 2,2,2-trichlorocarbonate, allyl carbonate, p-nitrophenylcarbonate, benzyl carbonate, p-nitrobenzyl carbonate,S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and2,4-dinitrophenylsulfenate ester (See, e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley-Interscience Publication, NewYork, (1981)). Suitable protecting groups for an amino group include,but are not limited to, 1,1-dimethyl-2,2,2-trichloroethyl carbamate,1-methyl-1-(4-biphenylyl)ethyl carbamate, 2-trimethylsilylethylcarbamate, 9-fluorenylmethyl carbamate, and tert-butyl carbamate (T. W.Greene et al., Protective Groups in Organic Synthesis, 309-405 (2d ed.1991)).

The halo acids 1 and the amines of formula Ar₂NH₂ are commerciallyavailable or can be prepared by methods known to those skilled in theart. Compounds of formula 3a-e can be prepared by methods known to thoseskilled in the art (See M. B. Smith and J. March, March's AdvancedOrganic Chemistry: Reaction Mechanisms and Structure, 805-807 (5^(th)ed. 2001); H. Fillon et al., Tett. Lett. 42:3843-46 (2001); M. Amadji etal., Tettrahedron 9:1657-60 (1998); and S. Billotte, Synlett. 379-380(1998)).

4.5.2 Methods for Making the Pyridylene Compounds where X is S

The Pyridylene Compounds where X is S can be obtained by reacting aPyridylene Compound where X is O, prepared as described above in section4.5.1, with Lawesson's reagent at a temperature of about 100° C. (See,e.g., J. March, Advanced Organic Chemistry, Reactions, Mechanisms, andStructure, 891-892 (4^(th) ed. 1992)).

4.6 Therapeutic Uses of the Pyridylene Compounds

In accordance with the invention, the Pyridylene Compounds areadministered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a Pyridylene Compound can beused to treat or prevent any condition treatable or preventable byinhibiting VR1. Examples of conditions that are treatable or preventableby inhibiting VR1 include, but are not limited to, pain, UI, an ulcer,IBD, and IBS.

In another embodiment, an effective amount of a Pyridylene Compound canbe used to treat or prevent any condition treatable or preventable byinhibiting mGluR5. Examples of conditions that are treatable orpreventable by inhibiting mGluR5 include, but are not limited to, pain,an addictive disorder, Parkinson's disease, parkinsonism, anxiety, apruritic condition, and psychosis.

In another embodiment, an effective amount of a Pyridylene Compound canbe used to treat or prevent any condition treatable or preventable byinhibiting mGluR1. Examples of conditions that are treatable orpreventable by inhibiting mGluR1 include, but are not limited to, pain,UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, and depression.

The Pyridylene Compounds can be used to treat or prevent acute orchronic pain. Examples of pain treatable or preventable using thePyridylene Compounds include, but are not limited to, cancer pain, laborpain, myocardial infarction pain, pancreatic pain, colic pain,post-operative pain, headache pain, muscle pain, arthritic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

The Pyridylene Compounds can also be used for treating or preventingpain associated with inflammation or with an inflammatory disease in ananimal. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response and/or a systemicinflammation. For example, the Pyridylene Compounds can be used to treator prevent pain associated with inflammatory diseases including, but notlimited to: organ transplant rejection; reoxygenation injury resultingfrom organ transplantation (see Grupp et al., J. Mol, Cell Cardiol.31:297-303 (1999)) including, but not limited to, transplantation of theheart, lung, liver, or kidney; chronic inflammatory diseases of thejoints, including arthritis, rheumatoid arthritis, osteoarthritis andbone diseases associated with increased bone resorption; inflammatorybowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome,and Crohn's disease; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disease of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory disease of the skin, including sclerodermatitis,psoriasis and eczema; inflammatory diseases of the central nervoussystem, including chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration and Alzheimer'sdisease, infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune diseases, including Type I and TypeII diabetes mellitus; diabetic complications, including, but not limitedto, diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), polyneuropathy,mononeuropathies, autonomic neuropathy, gangrene of the feet,atherosclerotic coronary arterial disease, peripheral arterial disease,nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems,and a skin or mucous membrane complication (such as an infection, a shinspot, a candidal infection or necrobiosis lipoidica diabeticorum);immune-complex vasculitis, and systemic lupus erythematosus (SLE);inflammatory disease of the heart, such as cardiomyopathy, ischemicheart disease hypercholesterolemia, and artherosclerosis; as well asvarious other diseases that can have significant inflammatorycomponents, including preeclampsia, chronic liver failure, brain andspinal cord trauma, and cancer. The Pyridylene Compounds can also beused for treating or preventing pain associated with inflammatorydisease that can, for example, be a systemic inflammation of the body,exemplified by gram-positive or gram negative shock, hemorrhagic oranaphylactic shock, or shock induced by cancer chemotherapy in responseto pro-inflammatory cytokines, e.g., shock associated withpro-inflammatory cytokines. Such shock can be induced, e.g., by achemotherapeutic agent that is administered as a treatment for cancer.

The Pyridylene Compounds can be used to treat or prevent UI. Examples ofUI treatable or preventable using the Pyridylene Compounds include, butare not limited to, urge incontinence, stress incontinence, overflowincontinence, neurogenic incontinence, and total incontinence.

The Pyridylene Compounds can be used to treat or prevent an ulcer.Examples of ulcers treatable or preventable using the PyridyleneCompounds include, but are not limited to, a duodenal ulcer, a gastriculcer, a marginal ulcer, an esophageal ulcer, and a stress ulcer.

The Pyridylene Compounds can be used to treat or prevent IBD, includingCrohn's disease and ulcerative colitis.

The Pyridylene Compounds can be used to treat or prevent IBS. Examplesof IBS treatable or preventable using the Pyridylene Compounds include,but are not limited to, spastic-colon-type IBS andconstipation-predominant IBS.

The Pyridylene Compounds can be used to treat or prevent an addictivedisorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and EatingDisorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse,Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence,Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-InducedMood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder, and Alcohol-RelatedDisorder not otherwise specified (NOS).

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, and Amphetamine Related Disorder not otherwise specified(NOS).

Cannabis-related disorders include, but are not limited to, CannabisDependence, Cannabis Abuse, Cannabis Intoxication, Cannabis IntoxicationDelirium, Cannabis-Induced Psychotic Disorder with delusions,Cannabis-Induced Psychotic Disorder with hallucinations,Cannabis-Induced Anxiety Disorder, and Cannabis Related Disorder nototherwise specified (NOS).

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, andCocaine Related Disorder not otherwise specified (NOS).

Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen Persisting Perception Disorder (Flashbacks),Hallucinogen-Induced Psychotic Disorder with delusions,Hallucinogen-Induced Psychotic Disorders with hallucinations,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-InducedSleep Disorder, Hallucinogen Related Disorder not otherwise specified(NOS).

Inhalant-related disorders include, but are not limited to, InhalantDependence, Inhalant Abuse, Inhalant Intoxication, Inhalant IntoxicationDelirium, Inhalant-Induced Psychotic Disorder with delusions,Inhalant-Induced Psychotic Disorder with hallucinations,Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder nototherwise specified (NOS).

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, OpioidIntoxication Delirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, and Opioid Related Disorder not otherwise specified(NOS).

The Pyridylene Compounds can be used to treat or prevent Parkinson'sdisease and parkinsonism and the symptoms associated with Parkinson'sdisease and parkinsonism, including but not limited to, bradykinesia,muscular rigidity, resting tremor, and impairment of postural balance.

The Pyridylene Compounds can be used to treat or prevent generalizedanxiety or severe anxiety and the symptoms associated with anxiety,including but not limited to, restlessness; tension; tachycardia;dyspnea; depression, including chronic “neurotic” depression; panicdisorder; agoraphobia and other specific phobias; eating disorders; andpersonality disorders.

The Pyridylene Compounds can be used to treat or prevent epilepsy,including but not limited to, partial epilepsy, generalized epilepsy,and the symptoms associated with epilepsy, including but not limited to,simple partial seizures, jacksonian seizures, complex partial(psychomotor) seizures, convulsive seizures (grand mal or tonic-clonicseizures), petit mal (absence) seizures, and status epilepticus.

The Pyridylene Compounds can be used to treat or prevent strokes,including but not limited to, ischemic strokes and hemorrhagic strokes.

The Pyridylene Compounds can be used to treat or prevent a seizure,including but not limited to, infantile spasms, febrile seizures, andepileptic seizures.

The Pyridylene Compounds can be used to treat or prevent a pruriticcondition, including but not limited to, pruritus caused by dry skin,scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvaeet ani, miliaria, insect bites, pediculosis, contact dermatitis, drugreactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The Pyridylene Compounds can be used to treat or prevent psychosis,including but not limited to, schizophrenia, including paranoidschizophrenia, hebephrenic or disorganized schizophrenia, catatonicschizophrenia, undifferentiated schizophrenia, negative or deficitsubtype schizophrenia, and non-deficit schizophrenia; a delusionaldisorder, including erotomanic subtype delusional disorder, grandiosesubtype delusional disorder, jealous subtype delusional disorder,persecutory subtype delusional disorder, and somatic subtype delusionaldisorder; and brief psychosis.

The Pyridylene Compounds can be used to treat or prevent a cognitivedisorder, including but not limited to, delirium and dementia such asmulti-infarct dementia, dementia pugilistica, dementia caused by AIDS,and dementia caused by Alzheimer's disease.

The Pyridylene Compounds can be used to treat or prevent a memorydeficiency, including but not limited to, dissociative amnesia anddissociative fugue.

The Pyridylene Compounds can be used to treat or prevent restrictedbrain function, including but not limited to, that caused by surgery oran organ transplant, restricted blood supply to the brain, a spinal cordinjury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.

The Pyridylene Compounds can be used to treat or prevent Huntington'schorea.

The Pyridylene Compounds can be used to treat or prevent ALS.

The Pyridylene Compounds can be used to treat or prevent retinopathy,including but not limited to, arteriosclerotic retinopathy, diabeticarteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

The Pyridylene Compounds can be used to treat or prevent a muscle spasm.

The Pyridylene Compounds can be used to treat or prevent a migraineincluding, but not limited to, migraine without aura (“commonmigraine”), migraine with aura (“classic migraine”), migraine withoutheadache, basilar migraine, familial hemiplegic migraine, migrainousinfarction, and migraine with prolonged aura.

The Pyridylene Compounds can be used to treat or prevent vomiting,including but not limited to, nausea vomiting, dry vomiting (retching),and regurgitation.

The Pyridylene Compounds can be used to treat or prevent dyskinesia,including but not limited to, tardive dyskinesia and biliary dyskinesia.

The Pyridylene Compounds can be used to treat or prevent depression,including but not limited to, major depression and bipolar disorder.

Applicants believe that the Pyridylene Compounds are antagonists forVR1.

The invention also relates to methods for inhibiting VR1 function in acell, comprising contacting a cell capable of expressing VR1 with anamount of a Pyridylene Compound effective to inhibit VR1 function in acell. This method can be used in vitro, for example, as an assay toselect cells that express VR1 and, accordingly, are useful as part of anassay to select compounds useful for treating or preventing pain, UI, anulcer, IBD, or IBS. The method is also useful for inhibiting VR1function in a cell in vivo, in an animal (e.g., a human), by contactinga cell of the animal with an effective amount of a Pyridylene Compound.In one embodiment, the method is useful for treating or preventing painin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing UI in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing anulcer in an animal in need thereof. In another embodiment, the method isuseful for treating or preventing IBD in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing IBSin an animal in need thereof.

Examples of tissue comprising cells capable of expressing VR1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express VR1 are known in theart.

Applicants believe that the Pyridylene Compounds are antagonists formGluR5.

The invention further relates to methods for inhibiting mGluR5 functionin a cell, comprising contacting a cell capable of expressing mGluR5with an amount of a Pyridylene Compound effective to inhibit mGluR5function in the cell. This method can be used in vitro, for example, asan assay to select cells that express mGluR5 and, accordingly, areuseful as part of an assay to select compounds useful for treating orpreventing pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, or psychosis. The method isalso useful for inhibiting mGluR5 function in a cell in vivo, in ananimal (e.g., a human), by contacting a cell, in an animal, with anamount of a Pyridylene Compound effective to inhibit mGluR5 function inthe cell. In one embodiment, the method is useful for treating orpreventing pain in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing an addictive disorder in ananimal in need thereof. In another embodiment, the method is useful fortreating or preventing Parkinson's disease in an animal in need thereof.In another embodiment, the method is useful for treating or preventingparkinsonism in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing anxiety in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing a pruritic condition in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing psychosis inan animal in need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glialcells of the central nervous system, particularly the brain, especiallyin the nucleus accumbens. Methods for assaying cells that express mGluR5are known in the art.

Applicants believe that the Pyridylene Compounds are antagonists formGluR1.

The invention also relates to methods for inhibiting mGluR1 function ina cell, comprising contacting a cell capable of expressing mGluR1 withan amount of a Pyridylene Compound effective to inhibit mGluR1 functionin the cell. This method can be used in vitro, for example, as an assayto select cells that express mGluR1 and, accordingly, are useful as partof an assay to select compounds useful for treating or preventing pain,UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety,epilepsy, stroke, a seizure, a pruritic condition, psychosis, acognitive disorder, a memory deficit, restricted brain function,Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, amigraine, vomiting, dyskinesia, or depression. The method is also usefulfor inhibiting mGluR1 function in a cell in vivo, in an animal (e.g., ahuman), by contacting a cell in an animal with an effective amount of aPyridylene Compound. In one embodiment, the method is useful fortreating or preventing pain in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing UI in ananimal in need thereof. In another embodiment, the method is useful fortreating or preventing an addictive disorder in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing Parkinson's disease in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing parkinsonismin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing anxiety in an animal in need thereof.In another embodiment, the method is useful for treating or preventingepilepsy in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing stroke in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing a seizure in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a pruriticcondition in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing psychosis in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a cognitive disorder in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing amemory deficit in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing restricted brain function inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing Huntington's chorea in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing ALS in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing dementia in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing retinopathy in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a musclespasm in an animal in need thereof. In another embodiment, the method isuseful for treating or preventing a migraine in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing vomiting in an animal in need thereof. In another embodiment,the method is useful for treating or preventing dyskinesia in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing depression in an animal in need thereof.

Examples of cells capable of expressing mGluR1 include, but are notlimited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are known in the art.

4.7 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Pyridylene Compounds are advantageouslyuseful in veterinary and human medicine. As described above, thePyridylene Compounds are useful for treating or preventing a Conditionin an animal in need thereof.

When administered to an animal, the Pyridylene Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a Pyridylene Compound, can be administeredorally. The Pyridylene Compounds of the invention can also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral, rectal, and intestinal mucosa, etc.) and can beadministered together with another therapeutically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the Pyridylene Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of the Pyridylene Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer thePyridylene Compounds locally. This can be achieved, for example, and notby way of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository orenema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the PyridyleneCompounds into the central nervous system or gastrointestinal tract byany suitable route, including intraventricular, intrathecal, andepidural injection, and enema. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Pyridylene Compounds can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the Pyridylene Compounds can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the Pyridylene Compounds can be delivered ina controlled-release system or sustained-release system (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled- or sustained-release systemsdiscussed in the review by Langer, Science 249:1527-1533 (1990) can beused. In one embodiment, a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N Engl. J.Med. 321:574 (1989)). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release (Langer and Wiseeds., 1974); Controlled Drug Bioavailability, Drug Product Design andPerformance (Smolen and Ball eds., 1984); Ranger and Peppas, J.Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)). In yet another embodiment, acontrolled- or sustained-release system can be placed in proximity of atarget of the Pyridylene Compounds, e.g., the spinal column, brain, orgastrointestinal tract, thus requiring only a fraction of the systemicdose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal. Such a pharmaceutical excipient canbe a liquid, such as water or an oil, including those of petroleum,animal, vegetable, or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. The pharmaceutical excipient canbe saline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to an animal. Water is a particularly useful excipient whenthe Pyridylene Compound is administered intravenously. Saline solutionsand aqueous dextrose and glycerol solutions can also be employed asliquid excipients, particularly for injectable solutions. Suitablepharmaceutical excipients also include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsions, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule(see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Pyridylene Compounds are formulated in accordancewith routine procedures as a composition adapted for oral administrationto human beings. Compositions for oral delivery can be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

In another embodiment, the Pyridylene Compounds can be formulated forintravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lidocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe Pyridylene Compounds are to be administered by infusion, they can bedispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the Pyridylene Compounds areadministered by injection, an ampule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

The Pyridylene Compounds can be administered by controlled-release orsustained-release means or by delivery devices that are known to thosein the art. Examples include, but are not limited to, those described inU.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;5,354,556; and 5,733,566, each of which is incorporated herein byreference. Such dosage forms can be used to provide controlled- orsustained-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known to those in the art, includingthose described herein, can be readily selected for use with the activeingredients of the invention. The invention thus encompasses single unitdosage forms suitable for oral administration such as, but not limitedto, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained-release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a Pyridylene Compound to treat or prevent the Condition or asymptom thereof in a minimum amount of time. Advantages of controlled-or sustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased patient compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the Pyridylene Compound, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Pyridylene Compound that promptly produces the desiredtherapeutic or prophylactic effect, and gradually and continuallyrelease other amounts of the Pyridylene Compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.To maintain a constant level of the Pyridylene Compound in the body, thePyridylene Compound can be released from the dosage form at a rate thatwill replace the amount of Pyridylene Compound being metabolized andexcreted from the body. Controlled- or sustained-release of an activeingredient can be stimulated by various conditions, including but notlimited to, changes in pH, changes in temperature, concentration oravailability of enzymes, concentration or availability of water, orother physiological conditions or compounds.

The amount of the Pryidylene Compound that is effective for thetreatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the Condition and can be decidedaccording to the judgment of a practitioner and/or each animal'scircumstances. Suitable effective dosage amounts, however, range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although they are typically about 100 mg/kg of body weight or less. Inone embodiment, the effective dosage amount ranges from about 0.01 mg/kgof body weight to about 100 mg/kg of body weight of a PryidyleneCompound, in another embodiment, about 0.02 mg/kg of body weight toabout 50 mg/kg of body weight, and in another embodiment, about 0.025mg/kg of body weight to about 20 mg/kg of body weight. In oneembodiment, an effective dosage amount is administered about every 24 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 h until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 h until the Condition is abated. In anotherembodiment, an effective dosage amount is administered about every 6 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 4 h until the Condition isabated. The effective dosage amounts described herein refer to totalamounts administered; that is, if more than one Pryidylene Compound isadministered, the effective dosage amounts correspond to the totalamount administered.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Pryidylene Compound in vitro, the amount effective for inhibitingthe VR1, mGluR5, or mGluR1 receptor function in a cell will typicallyrange from about 0.01 μg/L to about 5 mg/L, in one embodiment, fromabout 0.01 μg/L to about 2.5 mg/L, in another embodiment, from about0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about 0.01μg/L to about 0.25 mg/L of a solution or suspension of apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Pryidylene Compound isfrom about 0.01 μL to about 1 mL. In another embodiment, the volume ofsolution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Pryidylene Compound in vivo, the amount effective for inhibitingthe receptor function in a cell will typically range from about 0.01mg/kg of body weight to about 2500 mg/kg of body weight, although ittypically ranges from about 100 mg/kg of body weight or less. In oneembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of a Pryidylene Compound,in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kgof body weight, and in another embodiment, about 0.025 mg/kg of bodyweight to about 20 mg/kg of body weight. In one embodiment, an effectivedosage amount is administered about every 24 h. In another embodiment,an effective dosage amount is administered about every 12. In anotherembodiment, an effective dosage amount is administered about every 8. Inanother embodiment, an effective dosage amount is administered aboutevery 6 h. In another embodiment, an effective dosage amount isadministered about every 4 h.

The Pyridylene Compounds can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition in an animalin need thereof can further comprise administering to the animal beingadministered a Pyridylene Compound another therapeutic agent. In oneembodiment, the other therapeutic agent is administered in an effectiveamount.

The present methods for inhibiting VR1 function in a cell capable ofexpressing VR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent that may or may notinhibit VR1.

The present methods for inhibiting mGluR5 function in a cell capable ofexpressing mGluR5 can further comprise contacting the cell with aneffective amount of another therapeutic agent that may or may notinhibit mGluR5.

The present methods for inhibiting mGluR1 function in a cell capable ofexpressing mGluR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent that may or may notinhibit mGluR1.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention, whereanother therapeutic agent is administered to an animal, the minimaleffective amount of the Pyridylene Compound is less than its minimaleffective amount would be where the other therapeutic agent is notadministered. In this embodiment, without being bound by theory, it isbelieved that the Pyridylene Compounds and the other therapeutic agentact synergistically to treat or prevent a Condition.

The other therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, aβ-adrenergic blocker, an anticonvulsant, an antidepressant, aCa2+-channel blocker, an anticancer agent, an agent for treating orpreventing UI, an agent for treating or preventing an ulcer, an agentfor treating or preventing IBD, an agent for treating or preventing IBS,an agent for treating addictive disorder, an agent for treatingParkinson's disease and parkinsonism, an agent for treating anxiety, anagent for treating epilepsy, an agent for treating a stroke, an agentfor treating a seizure, an agent for treating a pruritic condition, anagent for treating psychosis, an agent for treating Huntington's chorea,an agent for treating ALS, an agent for treating a cognitive disorder,an agent for treating a migraine, an agent for inhibiting vomiting, anagent for treating dyskinesia, or an agent for treating depression, andmixtures thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996); andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19^(th) ed. 1995), which are hereby incorporated byreference in their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

The other therapeutic agent can also be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine,acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide,bietanautine, bromopride, buclizine, clebopride, cyclizine,dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H2antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H+, K+-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazine;mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, andfelbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating, inhibiting, orpreventing vomiting include, but are not limited to, 5-HT3 receptorantagonists such as odansteron, dolasetron, granisetron, andtropisetron; dopamine receptor antagonists such as prochlorperazine,thiethylperazine, chlorpromazin, metoclopramide, and domperidone;glucocorticoids such as dexamethasone; and benzodiazepines such aslorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A Pyridylene Compound and the other therapeutic agent combined can actadditively or, in one embodiment, synergistically. In one embodiment, aPyridylene Compound is administered concurrently with anothertherapeutic agent, for example, a composition comprising an effectiveamount of a Pyridylene Compound and an effective amount of anothertherapeutic agent can be administered. Alternatively, a compositioncomprising an effective amount of a Pyridylene Compound and a differentcomposition comprising an effective amount of another therapeutic agentcan be concurrently administered. In another embodiment, an effectiveamount of a Pyridylene Compound is administered prior or subsequent toadministration of an effective amount of another therapeutic agent. Inthis embodiment, the Pyridylene Compound is administered while the othertherapeutic agent exerts its therapeutic effect, or the othertherapeutic agent is administered while the Pyridylene Compound exertsits therapeutic effect for treating or preventing a Condition.

A composition of the invention is prepared by a method comprisingadmixing a Pyridylene Compound or a pharmaceutically acceptable salt anda pharmaceutically acceptable carrier or excipient. Admixing can beaccomplished using methods known for admixing a compound (or salt) and apharmaceutically acceptable carrier or excipient. In one embodiment, thePyridylene Compound is present in the composition in an effectiveamount.

4.8 Kits

The invention encompasses kits that can simplify the administration of aPyridylene Compound to an animal.

A typical kit of the invention comprises a unit dosage form of aPyridylene

Compound. In one embodiment, the unit dosage form is a container, whichcan be sterile, containing an effective amount of a Pyridylene Compoundand a pharmaceutically acceptable carrier or excipient. The kit canfurther comprise a label or printed instructions instructing the use ofthe Pyridylene Compound to treat or prevent a Condition. The kit canalso further comprise a unit dosage form of another therapeutic agent,for example, a second container containing an effective amount of theother therapeutic agent and a pharmaceutically acceptable carrier orexcipient. In another embodiment, the kit comprises a containercontaining an effective amount of a Pyridylene Compound, an effectiveamount of another therapeutic agent and a pharmaceutically acceptablecarrier or excipient. Examples of other therapeutic agents include, butare not limited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES 5.1 Example 1 Synthesis of Pyridylene Compound E35(a)

To a solution of 5-bromopyridine-2-carbonitrile (commercially availablefrom Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3equivalents of sodium hydroxide as a 1.5 M aqueous solution and theresulting solution was allowed to reflux at a temperature of about 85°C. until no further evolution of ammonia gas was detected. The resultingsolution was then concentrated under reduced pressure to provide aresidue. The residue was dissolved in water, acidified with acetic acid,and allowed to stir for about 16 h at a temperature of about 25° C. toprovide a solid precipitate. The solid was collected by vacuumfiltration and washed with acetone to provide5-bromopyridine-2-carboxylic acid (Compound B) as a solid.5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT,and 1 equivalent of EDCI were dissolved in DMF and combined with about1.1 equivalents of 4-tert-butylaniline (Compound C; commerciallyavailable from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resultingmixture was allowed to stir for about 2 h at about 25° C. The reactionmixture was then diluted with about 80 mL of 2N aqueous sodium hydroxideand extracted with ethyl acetate (3 extractions, 80 mL/extraction). Theethyl acetate layers were combined and the ethyl acetate was removedunder reduced pressure to provide a solid. The resulting solid wassuspended in water and filtered using vacuum filtration to provideCompound D as a solid. Compound D was dissolved in DMF (0.04M) and about3 equivalents of the zinc bromide Compound F (commercially availablefrom Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh₃)₄(commercially available from Sigma-Aldrich) were added to the solutionunder a nitrogen atmosphere, and the resulting reaction mixture wasallowed to stir for about 2 h at a temperature of about 100° C. Thesolvent was then removed under reduced pressure to provide PyridyleneCompound E35(a). Pyridylene Compound E35(a) was purified usingpreparative thin-layer chromatography with a 1:1 ethyl acetate:hexanemobile phase to provide purified Pyridylene Compound E35(a) as anoff-white solid (yield 47%).

The identity of Pyridylene Compound E35(a) was confirmed using ¹H NMR.

Compound E35(a): ¹H NMR (CDCl₃) δ: 10.000 (s, 1H), 8.807 (s, 1H), 8.596(d, 1H), 8.389 (d, 1H), 8.094 (dd, 1H), 7.732 (d, 2H), 7.654 (d, 1H),7.421 (d, 2H), 7.279 (m, 1H+CDCl₃), 2.418 (s, 3H), 1.341 (s, 9H).

5.2 Example 2 Synthesis of Pyridylene Compound E35(b)

Pyridylene Compound E35(b) was made by a procedure analogous to thatused to make Pyridylene Compound E35(a) in Example 1 except that6-chloronicotinic acid (Compound G), shown below:

was used in place of 5-bromopyridine-2-carboxylic acid (Compound B).6-Chloronicotinic acid (Compound G) was obtained by hydrolyzing6-chloronicotinic acid ethyl ester (commercially available fromSigma-Aldrich).

Pyridylene Compound E35(b) was obtained as a white solid (yield 22%).

The identity of Pyridylene Compound E35(b) was confirmed using ¹H NMR.

Compound E35(b): ¹H NMR (CDCl₃) S: 9.167-9.128 (s, 1H), 8.588-8.546 (d,1H), 8.322-8.277 (dd, 1H), 8.022-7.972 (d, 1H), 7.929-7.880 (s, 1H),7.675-7.634 (d, 1H), 7.614-7.556 (d, 1H), 7.453-7.395 (d, 1H),7.307-7.264 (m, 1H), 2.581-2.536 (s, 3H), 1.607-1.540 (s, 9H).

5.3 Example 3 Binding of Pyridylene Compounds to mGluR5

The following assay can be used to demonstrate that Pyridylene Compoundsbind to and modulate the activity of mGluR5.

Cell Cultures: Primary glial cultures are prepared from cortices ofSprague-Dawley 18 days old embryos. The cortices are dissected and thendissociated by trituration. The resulting cell homogenate is plated ontopoly-D-lysine precoated T175 flasks (BIOCOAT, commercially availablefrom Becton Dickinson and Company Inc. of Franklin Lakes, N.J.) inDulbecco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mMHEPES, and supplemented with 15% fetal calf serum (“FCS,” commerciallyavailable from Hyclone Laboratories Inc. of Omaha, Nebr.), and incubatedat 37° C. and 5% CO₂. After 24 hours, FCS supplementation is reduced to10%. On day six, oligodendrocytes and microglia are removed by stronglytapping the sides of the flasks. One day following this purificationstep, secondary astrocyte cultures are established by subplating onto 96poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes arewashed with serum free medium and then cultured in DMEM, withoutglutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermalgrowth factor (“EGF”), 1 mM sodium pyruvate, and 1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂.The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience15(9):6103-6109 (1995).

Assay Protocol: After 3-5 days incubation with EGF, the astrocytes arewashed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂PO₄, 2 mMCaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”)and loaded with the dye Fluo-4 (commercially available from MolecularProbes Inc. of Eugene, Oreg.) using 0.1 mL of Assay Buffer containingFluo-4 (3 mM final). After 90 minutes of dye loading, the cells are thenwashed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of AssayBuffer. The plates containing the astrocytes are then transferred to aFluorometric Imaging Plate reader (“FLIPR,” commercially available fromMolecular Devices Corporation of Sunnyvale, Calif.) for the assessmentof calcium mobilization flux in the presence of glutamate and in thepresence or absence of antagonist. After monitoring fluorescence for 15seconds to establish a baseline, DMSO solutions containing variousconcentrations of a Pyridylene Compound diluted in Assay Buffer (0.05 mLof 4× dilutions for competition curves) are added to the cell plate andfluorescence is monitored for 2 minutes. 0.05 mL of a 4× glutamatesolution (agonist) is then added to each well to provide a finalglutamate concentration in each well of 10 mM. Plate fluorescence isthen monitored for an additional 60 seconds after agonist addition. Thefinal DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine the IC₅₀ value. In eachexperiment, each data point is determined two times.

5.4 Example 4 In Vivo Assays for Prevention or Treatment of Pain

Test Animals: Each experiment uses rats weighing between 200-260 g atthe start of the experiment. The rats are group-housed and have freeaccess to food and water at all times, except prior to oraladministration of a Pyridylene Compound when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a Pyridylene Compound. The control group is administeredthe carrier for the Pyridylene Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Pyridylene Compound administered to the test group.

Acute Pain: To assess the actions of the Pyridylene Compounds for thetreatment or prevention of acute pain, the rat tail flick test can beused. Rats are gently restrained by hand and the tail exposed to afocused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a Pyridylene Compound. Data are expressed astail flick latency(s) and the percentage of the maximal possible effect(% MPE), i.e., 20 seconds, is calculated as follows:

${\% \mspace{14mu} M\; P\; E} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \right\rbrack}{\left( {20\mspace{14mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain: To assess the actions of the Pyridylene Compounds forthe treatment or prevention of inflammatory pain, the Freund's completeadjuvant (“FCA”) model of inflammatory pain is used. FCA-inducedinflammation of the rat hind paw is associated with the development ofpersistent inflammatory mechanical hyperalgesia and provides reliableprediction of the anti-hyperalgesic action of clinically usefulanalgesic drugs (L. Bartho et al., “Involvement of Capsaicin-sensitiveNeurones in Hyperalgesia and Enhanced Opioid Antinociception inInflammation,” Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670(1990)). The left hind paw of each animal is administered a 50 μLintraplantar injection of 50% FCA. 24 hour post injection, the animal isassessed for response to noxious mechanical stimuli by determining thePWT, as described below. Rats are then administered a single injectionof 1, 3, 10 or 30 mg/kg of either a Pyridylene Compound; 30 mg/kg of acontrol selected from Celebrex, indomethacin or naproxen; or carrier.Responses to noxious mechanical stimuli are then determined 1, 3, 5 and24 hours post administration. Percentage reversal of hyperalgesia foreach animal is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

Neuropathic Pain: To assess the actions of the Pyridylene Compounds forthe treatment or prevention of neuropathic pain, either the Seltzermodel or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Pyridylene Compoundfor the left rear paw of the animal. The animal can also be assessed forresponse to noxious thermal stimuli or for tactile allodynia, asdescribed below. The Chung model for neuropathic pain is described in S.H. Kim, “An Experimental Model for Peripheral Neuropathy Produced bySegmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy) as described inC. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Only theaffected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

5.5 Example 5 In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be usedto assess the anxiolytic activity of Pyridylene Compounds in rats ormice.

The Elevated Plus Maze Test: The elevated plus maze consists of aplatform with 4 arms, two open and two closed (50×10×50 cm enclosed withan open roof). Rats (or mice) are placed in the center of the platform,at the crossroad of the 4 arms, facing one of the closed arms. Timespent in the open arms vs the closed arms and number of open arm entriesduring the testing period are recorded. This test is conducted prior todrug administration and again after drug administration. Test resultsare expressed as the mean time spent in open arms and the mean number ofentries into open arms. Known anxiolytic drugs increase both the timespent in open arms and number of open arm entries. The elevated plusmaze test is described in D. Treit, “Animal Models for the Study ofAnti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews9(2):203-222 (1985).

The Shock-Probe Burying Test: For the shock-probe burying test thetesting apparatus consists of a plexiglass box measuring 40×30×40 cm,evenly covered with approximately 5 cm of bedding material (odorabsorbent kitty litter) with a small hole in one end through which ashock probe (6.5 cm long and 0.5 cm in diameter) is inserted. Theplexiglass shock probe is helically wrapped with two copper wiresthrough which an electric current is administered. The current is set at2 mA. Rats are habituated to the testing apparatus for 30 min on 4consecutive days without the shock probe in the box. On test day, ratsare placed in one corner of the test chamber following drugadministration. The probe is not electrified until the rat touches itwith its snout or fore paws, at which point the rat receives a brief 2mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra.

5.6 Example 6 In Vivo Assays for Prevention or Treatment of an AddictiveDisorder

The conditioned place preference test or drug self-administration testcan be used to assess the ability of Pyridylene Compounds to attenuatethe rewarding properties of known drugs of abuse.

The Conditioned Place Preference Test: The apparatus for the conditionedplace preference test consists of two large compartments (45×45×30 cm)made of wood with a plexiglass front wall. These two large compartmentsare distinctly different. Doors at the back of each large compartmentlead to a smaller box (36×18×20 cm) made of wood, painted grey, with aceiling of wire mesh. The two large compartments differ in terms ofshading (white vs black), level of illumination (the plexiglass door ofthe white compartment is covered with aluminum foil except for a windowof 7×7 cm), texture (the white compartment has a 3 cm thick floor board(40×40 cm) with nine equally spaced 5 cm diameter holes and the blackhas a wire mesh floor), and olfactory cues (saline in the whitecompartment and 1 mL of 10% acetic acid in the black compartment). Onhabituation and testing days, the doors to the small box remain open,giving the rat free access to both large compartments.

The first session that a rat is placed in the apparatus is a habituationsession and entrances to the smaller grey compartment remain open givingthe rat free access to both large compartments. During habituation, ratsgenerally show no preference for either compartment. Followinghabituation, rats are given 6 conditioning sessions. Rats are dividedinto 4 groups: carrier pre-treatment+carrier (control group), PyridyleneCompound pre-treatment+carrier, carrier pre-treatment+morphine,Pyridylene Compound pre-treatment+morphine. During each conditioningsession the rat is injected with one of the drug combinations andconfined to one compartment for 30 min. On the following day, the ratreceives a carrier+carrier treatment and is confined to the other largecompartment. Each rat receives three conditioning sessions consisting of3 drug combination-compartment and 3 carrier-compartment pairings. Theorder of injections and the drug/compartment pairings arecounterbalanced within groups. On the test day, rats are injected priorto testing (30 min to 1 hour) with either morphine or carrier and therat is placed in the apparatus, the doors to the grey compartment remainopen and the rat is allowed to explore the entire apparatus for 20 min.The time spent in each compartment is recorded. Known drugs of abuseincrease the time spent in the drug-paired compartment during thetesting session. If the Pyridylene Compound blocks or reduces theacquisition of morphine conditioned place preference (reward), therewill be no difference or less of a difference in time spent in each sidein rats pre-treated with a Pyridylene Compound and the group will not bedifferent from the group of rats that was given carrier+carrier in bothcompartments. Data will be analyzed as time spent in each compartment(drug combination-paired vs carrier-paired). Generally, the experimentis repeated with a minimum of 3 doses of a Pyridylene Compound.

The Drug Self-Administration Test: The apparatus for the drugself-administration test is a standard commercially available operantconditioning chamber. Before drug trials begin rats are trained to pressa lever for a food reward. After stable lever pressing behavior isacquired, rats are tested for acquisition of lever pressing for drugreward. Rats are implanted with chronically indwelling jugular cathetersfor i.v. administration of compounds and are allowed to recover for 7days before training begins. Experimental sessions are conducted dailyfor 5 days in 3 hour sessions. Rats are trained to self-administer aknown drug of abuse, such as morphine. Rats are then presented with twolevers, an “active” lever and an “inactive” lever. Pressing of theactive lever results in drug infusion on a fixed ratio 1 (FR1) schedule(i.e., one lever press gives an infusion) followed by a 20 second timeout period (signaled by illumination of a light above the levers).Pressing of the inactive lever results in infusion of excipient.Training continues until the total number of morphine infusionsstabilizes to within ±10% per session. Trained rats are then used toevaluate the effect of Pyridylene Compounds pre-treatment on drugself-administration. On test day, rats are pre-treated with a PyridyleneCompound or excipient and then are allowed to self-administer drug asusual. If the Pyridylene Compound blocks or reduces the rewardingeffects of morphine, rats pre-treated with the Pyridylene Compound willshow a lower rate of responding compared to their previous rate ofresponding and compared to excipient pre-treated rats. Data are analyzedas the change in number of drug infusions per testing session (number ofinfusions during test session−number of infusions during trainingsession).

5.7 Example 7 Functional Assay for Characterizing mGluR1 AntagonisticProperties

Functional assays for the characterization of mGluR1 antagonisticproperties are known in the art. For example, the following procedurecan be used.

A CHO-rat mGluR1 cell line is generated using cDNA encoding rat mGluR1receptor (M. Masu and S, Nakanishi, Nature 349: 760-765 (1991)). ThecDNA encoding rat mGluR1 receptor can be obtained from, e.g., Prof. S,Nakanishi (Kyoto, Japan).

40,000 CHO-rat mGluR1 cells/well are plated into a Costar 3409, black,clear bottom, 96 well, tissue culture treated plate (commerciallyavailable from Fisher Scientific of Chicago, Ill.) and are incubated inDulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented withglutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12h. The CHO-rat mGluR1 cells are then washed and treated with Optimemmedium (commercially available from Invitrogen, Carlsbad, Calif.) andincubated for a time period ranging from 1 to 4 hours prior to loadingthe cells with the dye Fluo-4. After incubation, the cell plates arewashed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 μM,NaH₂PO₄, 2 mM CaCl₂, 5 mMNaHCO₃, 8 mM HEPES, and 10 mM glucose, pH 7.4)and incubated with 3 μM Fluo-4 in 0.1 mL loading buffer for 90 mM. Thecells are then washed twice with 0.2 mL loading buffer, resuspended in0.1 mL of loading buffer, and transferred to a FLIPR for measurement ofcalcium mobilization flux in the presence of glutamate and in thepresence or absence of a Pyridylene Compound.

To measure calcium mobilization flux, fluoresence is monitored for about15 s to establish a baseline and DMSO solutions containing variousconcentrations of a Pyridylene Compound ranging from about 50 μM toabout 0.8 nM diluted in loading buffer (0.05 mL of a 4× dilution) areadded to the cell plate and fluoresence is monitored for about 2 min.0.05 mL of a 4× Glutamate solution (agonist) is then added to each wellto provide a final glutamate concentration in each well of 10 μM andfluoresence is monitored for about 1 additional mM. The final DMSOconcentration in the assay is 1%. In each experiment fluoresence ismonitored as a function of time and the data is analyzed using anon-linear regression to determine the IC₅₀ value. In each experimenteach data point is determined twice.

5.8 Example 8 Binding of Pyridylene Compounds to VR1

Methods for assaying compounds capable of inhibiting VR1 are known tothose skilled in the art, for example, those methods disclosed in U.S.Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 toMcIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al.

Binding of Compound E35(a) to VR1: Assay Protocol

Human VR1 Cloning: Human spinal cord RNA (commercially available fromClontech, Palo Alto, Calif.) was used. Reverse transcription wasconducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase(commercially available from Invitrogen) and oligo dT primers asdetailed in its product description. Reverse transcription reactionswere incubated at 55° C. for 1 h, heat-inactivated at 85° C. for 5 min,and RNase H-treated at 37° C. for 20 min.

Human VR1 cDNA sequence was obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences were removed and flanking exonic sequences were joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human VR1 were designed as follows: forward primer,GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer,GAAGATCTTCGGGGACAGTGACGGTTGGATGT.

PCR of VR1 was performed on one tenth of the Reverse transcriptionreaction mixture using Expand Long Template Polymerase and Expand Buffer2 in a final volume of 50 μL according to the manufacturer'sinstructions (Roche Applied Sciences, Indianapolis, Ind.). Afterdenaturation at 94° C. for 2 min, PCR amplification was performed for 25cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68° C. for 3 minfollowed by a final incubation at 72° C. for 7 min to complete theamplification. A PCR product of ˜2.8 kb was gel-isolated using a 1.0%agarose, Tris-Acetate gel containing 1.6 μg/mL of crystal violet andpurified with a S.N.A.P. UV-Free Gel Purification Kit (commerciallyavailable from Invitrogen). The VR1 PCR product was cloned into thepIND/V5-His-TOPO vector (commercially available from Invitrogen)according to the manufacturer's instructions. DNA preparations,restriction enzyme digestions, and preliminary DNA sequencing wereperformed according to standard protocols. Full-length sequencingconfirmed the identity of the human VR1.

Generation of Inducible Cell Lines: Unless noted otherwise, cell culturereagents were purchased from Life Technologies of Rockville, Md. HEK293-EcR cells expressing the ecdysone receptor (commercially availablefrom Invitrogen) were cultured in Growth Medium (Dulbecco's ModifiedEagles Medium containing 10% fetal bovine serum (commercially availablefrom HYCLONE, Logan, Utah), 1× penicillin/streptomycin, 1× glutamine, 1mM sodium pyruvate and 400 μg/mL Zeocin (commercially available fromInvitrogen)). The VR1-pIND constructs were transfected into theHEK293-EcR cell line using Fugene transfection reagent (commerciallyavailable from Roche Applied Sciences, Basel, Switzerland). After 48 h,cells were transferred to Selection Medium (Growth Medium containing 300μg/mL G418 (commercially available from Invitrogen)). Approximately 3weeks, later individual Zeocin/G418 resistant colonies were isolated andexpanded. To identify functional clones, multiple colonies were platedinto 96-well plates and expression was induced for 48 h using SelectionMedium supplemented with 5 μM ponasterone A (“PonA”) (commerciallyavailable from Invitrogen). On the day of assay, cells were loaded withFluo-4 (a calcium-sensitive dye that is commercially available fromMolecular Probes) and CAP-mediated calcium influx was measured using aFLIPR as described below. Functional clones were re-assayed, expanded,and cryopreserved.

pH-Based Assay: Two days prior to performing this assay, cells wereseeded on poly-D-lysine-coated 96-well clear-bottom black plates(commercially available from Becton-Dickinson) at 75,000 cells/well ingrowth media containing 5 μM PonA to induce expression. On the day ofthe assay, the plates were washed with 0.2 mL 1× Hank's Balanced SaltSolution (commercially available from Life Technologies) containing 1.6mM CaCl₂ and 20 mM HEPES, pH 7.4 (“wash buffer”), and loaded using 0.1mL of wash buffer containing Fluo-4 (3 μM final concentration,commercially available from Molecular Probes). After 1 h, the cells werewashed twice with 0.2 mL wash buffer and resuspended in 0.05 mL 1×Hank's Balanced Salt Solution containing 3.5 mM CaCl₂ and 10 mM Citrate,pH 7.4 (“assay buffer”). Plates were then transferred to a FLIPR forassay. Compound E35(a) was diluted in assay buffer, and 50 mL of theresultant solution were added to the cell plates and the solutionmonitored for two minutes. The final concentration of Compound E35(a)ranged from about 50 μM to about 3 μM. Agonist buffer (wash buffertitrated with 1N HCl to provide a solution having a pH of 5.5 when mixed1:1 with assay buffer) (0.1 mL) was then added to each well, and theplates were incubated for 1 additional minute. Data were collected overthe entire time course and analyzed using Excel and Graph Pad Prism.Compound E35(a) when assayed according to this protocol had an IC₅₀ of825.5±247.8 nM (n=4).

Capsaicin-Based Assay: Two days prior to performing this assay, cellswere seeded in poly-D-lysine-coated 96-well clear-bottom black plates(50,000 cells/well) in growth media containing 5 μM PonA to induceexpression. On the day of the assay, the plates were washed with 0.2 mL1× Hank's Balanced Salt Solution containing 1 mM CaCl₂ and 20 mM HEPES,pH 7.4, and cells were loaded using 0.1 mL of wash buffer containingFluo-4 (3 μM final). After one hour, the cells were washed twice with0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. Theplates were transferred to a FLIPR for assay. 50 μL of Compound E35(a)diluted with assay buffer were added to the cell plates and incubatedfor 2 min. The final concentration of Compound E35(a) ranged from about50 μM to about 3 μM. Human VR1 was activated by the addition of 50 μL ofcapsaicin (400 nM), and the plates were incubated for an additional 3min. Data were collected over the entire time course and analyzed usingExcel and GraphPad Prism. Compound E35(a) when assayed according to thisprotocol had an IC₅₀ of 65.5±17.3 nM (n=3).

The results of the pH-based assay and the capsaicin-based assaydemonstrate that Compound E35(a), an illustrative Pyridylene Compound,binds to and modulates the activity of human VR1 and accordingly isuseful for treating or preventing pain, UI, an ulcer, IBD, or IBS in ananimal.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: Ar₁ is

Ar₂ is

X is O or S; R₁ is -halo, —CH₃, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);each R₂ is independently: (a) -halo, —OH, —NH₂, —CN, or —NO₂; (b)—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups; or(c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl,each of which is unsubstituted or substituted with one or more R₆groups; each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂;(b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or (c) -phenyl, -naphthyl,—(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with one or more R₆ groups; each R₅ isindependently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃,—NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR_(S), —S(O)R₇, or —S(O)₂R₇; each R₆ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR_(S), —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR_(S),—S(O)R₇, or —S(O)₂R₇; each R₇ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,—OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR_(S), —S(O)R₇, or —S(O)₂R₇; each R₁₁ isindependently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —COR_(S), —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR_(S),—S(O)R_(B), or —S(O)₂R₇; each halo is independently —F, —Cl, —Br, or —I;m is an integer ranging from 0 to 3; o is an integer ranging from 0 to4; p is an integer ranging from 0 to 2; q is an integer ranging from 0to 6; r is an integer ranging from 0 to 5; and s is an integer rangingfrom 0 to
 4. 2. The compound of claim 1, wherein p is 1 and R₂ is—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups. 3.The compound of claim 2, wherein R₂ is —(C₁-C₁₀)alkyl which issubstituted with two R₅ groups.
 4. The compound of claim 1, wherein: Ar₂is

X is O; and R₁ is —F, —Cl, —CH₃ or —CF₃.
 5. The compound of claim 4,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 6. The compound of claim 5,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups. 7.The compound of claim 4, wherein: m is 0; r is 1; and R₈ is—(C₁-C₆)alkyl, -halo, —OCF₃, or —CF₃.
 8. The compound of claim 7,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 9. The compound of claim 8,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.10. The compound of claim 7, wherein the —(C₁-C₆)alkyl is a tert-butylgroup, optionally substituted at the para-position of Ar₂.
 11. Thecompound of claim 1, wherein: Ar₂ is

X is O; R₁ is —CH₃, —CF₃, —Cl, —Br, —I, or —F; m is 0; (R₈)_(a) is —H;and (R₈)_(b) is —H, —CH₃, —OCH₃, —CF₃, —OCF₃, —OCH₂CH₃, iso-propyl,tert-butyl, —Br, —I, or —F.
 12. The compound of claim 11, wherein p is 1and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 13. The compound of claim 12,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.14. The compound of claim 11, wherein R₁ is —CH₃, —CF₃, or —Cl and(R₈)_(b) is —Cl, —F, —CF₃, —OCF₃ or tert-butyl.
 15. The compound ofclaim 1, wherein: Ar₂ is

X is O; and R₁ is —F, —Cl, —CH₃ or —CF₃.
 16. The compound of claim 15,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 17. The compound of claim 16,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.18. The compound of claim 15, wherein: m is 0; o is 1; and R₈ is—(C₁-C₆)alkyl or -halo.
 19. The compound of claim 18, wherein p is 1 andR₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₁₋₈—C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 20. The compound of claim 19,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.21. A composition comprising the compound or a pharmaceuticallyacceptable salt of the compound of claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 22. An in vitro method for inhibitingVR1 function in a cell comprising: contacting a cell expressing VR1 invitro with a compound of claim 1, or a pharmaceutically acceptable saltthereof, in an amount sufficient to reduce calcium ion mobilization intosaid cell treated with an activator of VR1 as compared to said cellexpressing VR1 in vitro treated with an activator of VR1 and notcontacted with said compound.
 23. The method of claim 22, wherein saidcalcium ion mobilization is reduced by 50% or more.
 24. A method fortreating pain in an animal, comprising administering to an animal inneed thereof an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim
 1. 25. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: Ar₁ is

Ar₂ is

X is O or S; R₁ is -halo, —CH₃, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);each R₂ is independently: (a) -halo, —OH, —NH₂, —CN, or —NO₂; (b)—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups; or(c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heteroaryl,each of which is unsubstituted or substituted with one or more R₆groups; each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂;(b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or (c) -phenyl, -naphthyl,—(C₁₄)aryl or -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with one or more R₆ groups; each R₅ isindependently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃,—NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R_(T), or —S(O)₂R₇; each R₆ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R_(B), or —S(O)₂R₇; each R₇ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,—OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R_(B), or —S(O)₂R₇; each R₁₁ isindependently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇; each halo is independently —F, —Cl, —Br, or —I; m is aninteger ranging from 0 to 3; o is an integer ranging from 0 to 4; p isan integer ranging from 0 to 2; q is an integer ranging from 0 to 6; ris an integer ranging from 0 to 5; and s is an integer ranging from 0 to4.
 26. The compound of claim 25, wherein p is 1 and R₂ is—(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups. 27.The compound of claim 26, wherein R₂ is —(C₁-C₁₀)alkyl which issubstituted with two R₅ groups.
 28. The compound of claim 25, wherein:Ar₂ is

X is O; and R₁ is —F, —CH₃ or —CF₃.
 29. The compound of claim 28,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 30. The compound of claim 29,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.31. The compound of claim 28, wherein: m is 0; r is 1; and R₈ is—(C₁-C₆)alkyl, -halo, —OCF₃, or —CF₃.
 32. The compound of claim 31,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 33. The compound of claim 32,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.34. The compound of claim 31, wherein the —(C₁-C₆)alkyl is a tert-butylgroup, optionally substituted at the para-position of Ar₂.
 35. Thecompound of claim 25, wherein: Ar₂ is

X is 0; R₁ is —CH₃, —CF₃, —Cl, —Br, —I, or —F; m is 0; (R₈)_(a) is —H;and (R₈)_(b) is —H, —CH₃, —OCH₃, —CF₃, —OCF₃, —OCH₂CH₃, iso-propyl,tert-butyl, —Cl, —Br, —I, or —F.
 36. The compound of claim 35, wherein pis 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 37. The compound of claim 36,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.38. The compound of claim 35, wherein R₁ is —CH₃, —CF₃, or —Cl and(R₈)_(b) is —Cl, —F, —CF₃, —OCF₃ or tert-butyl.
 39. The compound ofclaim 25, wherein: Ar₂ is

X is O; and R₁ is —F, —Cl, —CH₃ or —CF₃.
 40. The compound of claim 39,wherein p is 1 and R₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,—(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 41. The compound of claim 40,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.42. The compound of claim 39, wherein: m is 0; o is 1; and R₈ is—(C₁-C₆)alkyl or -halo.
 43. The compound of claim 42, wherein p is 1 andR₂ is —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl, —(C_(r)C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups.
 44. The compound of claim 43,wherein R₂ is —(C₁-C₁₀)alkyl which is substituted with two R₅ groups.45. A composition comprising the compound or a pharmaceuticallyacceptable salt of the compound of claim 25 and a pharmaceuticallyacceptable carrier or excipient.
 46. An in vitro method for inhibitingVR1 function in a cell comprising: contacting a cell expressing VR1 invitro with a compound of claim 25, or a pharmaceutically acceptable saltthereof, in an amount sufficient to reduce calcium ion mobilization intosaid cell treated with an activator of VR1 as compared to said cellexpressing VR1 in vitro treated with an activator of VR1 and notcontacted with said compound.
 47. The method of claim 46, wherein saidcalcium ion mobilization is reduced by 50% or more.
 48. A method fortreating pain in an animal, comprising administering to an animal inneed thereof an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound of claim 25.